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NPCs, short for Non-Player Characters, generally fall into two main areas: static, friendly characters that offer missions and/or generic dialogue responses; and mobile, hostile NPCs - enemies, and often game bosses - with a small amount of unique text or voiced dialogue to give them flavour.
- Athena - Crimson Lance defector.
- Mr. Blake - The vice president of the Hyperion corporation, and sinister benefactor in Tartarus Station.
- Chuck Durden - Owner of the Circle Of Slaughter in the Rust Commons West.
- Commandant Steele - Leader of the Crimson Lance on Pandora prior to the opening of the Vault.
- Crazy Earl - Shut-in who lives in Crazy Earl's Scrapyard. He has a pet Skag called Skrappy.
- Dr. Ned - Who is totally not Dr. Zed. Resides in Jakobs Cove.
- Dr. Zed - Resident doctor of Fyrestone, he later moves to New Haven - then T-Bone Junction.
- Erik Franks - New Haven resident (who wishes he wasn't) with a noticeable appreciation for pornography. Also a loyal follower of Taylor Kobb.
- Ernest Whitting - A renowned hunter who lives near the Arid Badlands entrance to the Dahl Headlands.
- General Knoxx - Crimson Lance general. Titular character of the third DLC, The Secret Armory of General Knoxx.
- Helena Pierce - Settlement administrator based out of New Haven. She has an artificial left arm.
- Hudson Johns - Custodian of the Middle of Nowhere Bounty Board.
- Jaynis Kobb - Feuding brother of Taylor Kobb.
- Lucky Zaford - Runs Lucky's Last Chance Watering Hole.
- Mad Moxxi - Owner of The Underdome. Titular character of the second DLC, Mad Moxxi's Underdome Riot.
- Marcus Kincaid - Narrator, bus driver, and arms dealer.
- Patricia Tannis - Former scientific adviser for the Dahl Corporation, now obsessed with finding The Vault.
- Rade Zayben - Owner of the Circle Of Death in the Arid Badlands.
- Scooter - Auto-mechanic who maintains the Catch-a-Ride system on Pandora.
- Shep Sanders - Friend of Dr. Zed who needs help with a few missions.
- Stance Von Kofsky - Lone gardener in the Rust Commons East.
- Taylor Kobb - Feuding brother of Jaynis Kobb.
- T.K. Baha - A blind widower who lives just outside Fyrestone, near Skag Gully. He has an artificial leg.
- Zach - The Director of the Circle of Duty.
- Claptrap - A small robot that introduces players to the game.
- Angel - The Guardian Angel from Borderlands returns to continue her cryptic machinations.
- Brick - One of the original Vault Hunters and a former Crimson Raider, now a leader of the Slab bandit gang.
- Crazy Earl - The shut-in proprietor of Sanctuary's Black Market.
- Captain Scarlett - Benefactor and antagonist pirate leader in Wurmwater.
- Dr. Zed - Sanctuary's "doctor".
- Ellie - Moxxi's daughter and Scooter's sister, mechanic for the Vault Hunters.
- Handsome Jack - President of Hyperion and the game's main antagonist.
- Herbert - Ex-pirate, lecher, and hermit.
- Lilith - One of the original Vault Hunters and the co-leader of the Crimson Raiders.
- Mad Moxxi - Bar hostess for Moxxi's in Sanctuary.
- Marcus Kincaid - The arms dealer from the first game based in Sanctuary.
- Michael Mamaril - A mysterious item distributor who visits Sanctuary from time to time.
- Mick Zaford - Publican and head of the Zaford clan.
- Mordecai - One of the original Vault Hunters and a scout for the Crimson Raiders.
- Patricia Tannis - Former Dahl scientist working for the Crimson Raiders.
- Roland - One of the original Vault Hunters and the leader of the Crimson Raiders.
- Scooter - Sanctuary's resident engineer and mechanic.
- Shade - Deranged and thirsty survivor of Oasis.
- Sir Hammerlock - A travelling hunter on research expeditions for his almanac.
- Tector & Jimbo Hodunk - Redneck speedway owners and heads of the Hodunk clan.
- C3n50r807 - An anti-piracy loader in Washburne Refinery.
- Claptrap - The Claptrap unit from Fyrestone, and the last of his kind.
- Innuendobot 5000 - A reprogrammed loader in Ore Chasm.
- Mal - A loader that desires to become human.