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Principal Brian Lewis is the head principal at Pearl Bailey High School and father of Janet Lewis. In "An Apocalypse to Remember", he is seen sitting with a woman and younger child at the Chicken or Fish Banquet Hall. In "The Worst Stan", it was revealed that he was in prison where he acquired Tracey Bryant as his "prison wife" after beating up Tracy's then current "husband". Stan beats up Brian to acquire Tracey so that Brian's planned wedding to Ellen Riggs may proceed but the wedding is stopped by Stan and Ellen marries Tracey herself.
Throughout the series, Lewis has done and said many very disturbing actions within his role as a principal.
- In "Escape from Pearl Bailey" he creates a mob of students to chase Steve and his friends.
- In "Bully for Steve" he's seen drinking beer during school hours and urinating at the basketball court.
- In "You Debt Your Life" is hinted at being a pedophile when he shows a fascination for young girls. In the same episode, he began to wish on how he stayed a drug runner which was heard by the whole school.
- In "I Am the Walrus" he has a restraining order against him for sexually harassing an art teacher.
- In "License to Till" he assaults Steve with a coffee pot.
- In "Home Wrecker" he knocks items out of the students' hands, sexually harasses female employees, takes students for illegal gambling, locks them in a car for hours, and even offers the kids up to be killed.
- He finds a bookie who will bet on anything in "The Wrestler" including when a student will get her period and on preschoolers drawing with crayons. When one girl draws out of the lines, Lewis curses her in front of her parents.
- In "100 A.D." He claimed he couldn't return to his job because he took a dump on his desk before stripping into a beach thong.
- The American Dad! staff were surprised over how much of a fan favorite the Principal Lewis character became. 
- He keeps $500 sticking out of his pocket to make the students think he is rich in "Pulling Double Booty".
- He is shown to be "ashamed of Janet for more reasons than you can imagine" in "Escape from Pearl Bailey".
- In "Jenny Fromdabloc," he attempts to sell belt buckles, one containing a bird that closely resembles Tweety looking indignant at a cross over the caption "There Is No God". He notes that Tweety's eyes are red from smoking weed.
- Principal Lewis lives alone in a messy house as seen in "I Am the Walrus" and "Hot Water". In addition, in "I Am the Walrus" he mentions that the messy house is the result of what happens when you try to strike some sense into your lady and his daughter Janet Lewis does not appear to live with him. In "The Worst Stan", he is set up to be married by Stan to school superintendent Ellen Riggs.
- In "The Worst Stan", Principal Lewis reveals that his family was the inspiration for the television show Diff'rent Strokes including many of the events depicted on the show. His step-father is named Mr. Druffel and he has a brother named William.
- In "National Treasure 4: Baby Franny: She's Doing Well: The Hole Story", Brian appears as a strongman on Greg and Terry's television show Morning Glory. As he tears a phone book in two, he proclaims that his strength come from above.
- Brian stars as "Black Villain" in "For Black Eyes Only".
- Principal Lewis and Marguerite appear during "He's Got a Kink" in "The Missing Kink". Stan also invites them over to watch him have kinky sex with Francine, some of which horrifies them.
- When in inopportune wish by Stan that he had Lewis' single lifestyle is granted in "Dreaming of a White Porsche Christmas", Lewis inherits Stan's job and family in return.
- While having an affair with Mrs. Lonstein in "Criss-Cross Applesauce: The Ballad Of Billy Jesusworth", Lewis finds out she is having another affair and shoots the closet, wounding Greg Corbin. He is quickly surrounded by several other neighbors whom he discovers are also having affairs with her.
- "Pilot (American Dad!)"
- "Deacon Stan, Jesus Man"
- "A Smith In The Hand"
- "The American Dad After School Special" (mentioned)
- "Iced, Iced Babies"
- "Black Mystery Month"
- "An Apocalypse to Remember"
- "Red October Sky"
- "Escape from Pearl Bailey"
- "Phantom of the Telethon"
- "Family Affair"
- "Roy Rogers McFreely"
- "Daddy Queerest"
- "In Country...Club"
- "Shallow Vows"
- "Bully for Steve"
- "100 A.D."
- "You Debt Your Life"
- "I Am the Walrus"
- "School Lies"
- "License to Till"
- "Jenny Fromdabloc"
- "Home Wrecker"
- "Hot Water"
- "A Ward Show"
- "The Worst Stan"
- "Virtual In-Stanity"
- "The Wrestler"
- "Ricky Spanish"
- "National Treasure 4: Baby Franny: She's Doing Well: The Hole Story"
- "Finger Lenting Good"
- "Naked to the Limit, One More Time"
- "For Black Eyes Only"
- "Spelling Bee My Baby"
- "The Missing Kink"
- "Steve and Snot's Test-Tubular Adventure"
- "News Glance With Genevieve Vavance"
- "Scents and Sensei-bility"
- "Dreaming of a White Porsche Christmas"
- "The Life Aquatic With Steve Smith"
- "Stan-Dan Deliver"
- "The Two Hundred"
- "Widow's Pique"
- "Criss-Cross Applesauce: The Ballad Of Billy Jesusworth"
- "Mine Struggle"
- "Garfield and Friends"
- "Fight and Flight"