The Jefferson Motel is a motel located in Jefferson, Los Santos; and is the main setting of Reuniting the Families. The motel has a number of rooms and a Sprunk vending machine, allowing the player to replenish Carl Johnson's health (at any point of the game). The motel is the meeting place for the Grove Street Families, Seville Boulevard Families and Temple Drive Families in Reuniting the Families. The meeting, aimed at re-uniting the families, is ambushed by the police. The southern wall of the motel also has a gang tag that can be sprayed, there is also an MP5 on the roof of the hotel. Jefferson, the district the motel is in, is controlled by the Ballas in 1992, although not many Ballas patrol the Jefferson Motel, which makes it harder to take over.
- In The Lost and Damned, during the mission Shifting Weight, the character Malc makes reference to a Jefferson Motel, joking that they should go to the Jefferson Motel for some light bondage, although he is likely referring to a different motel in Liberty City.
- A save icon can be seen through a skylight in the 2nd lobby (the one with the knocked down table) of the hotel. It belongs to the Hashbury Safehouse. You can jump through the skylight and enter the Interiors Universe by activating the Super Jump Cheat, jumping onto a potted plant on one side of the lobby, and then jumping through the skylight. If aimed correctly, you will jump through the skylight and appear on top of the room and you will be able to see the whole interior of the hotel.