Normally the winner of the Senate seat in 2006 would be running for reelection in 2012. This page lists races where that is not the case, either because the 2006 winner is retiring in 2012 or because he or she has resigned or died and a special election is being held in 2012 or was held in 2008 or 2010. Seats like these tend to be more competitive than usual. The colors represent the incumbent party.
| State | Incumbent | Party | Open? | Notes |
| AZ | Jon Kyl | GOP | Yes | He could have easily won but decided against it |
| CT | Joe Lieberman | Ind | Yes | He had almost no chance of winning so he retired |
| HI | Daniel Akaka | Dem | Yes | He retired due to old age |
| IN | Richard Lugar | GOP | Yes | He was defeated in a primary |
| MA | Scott Brown | GOP | No | He won a special election after Ted Kennedy died |
| ME | Olympia Snowe | GOP | Yes | She was just disgusted with how the Senate has become completely dysfunctional |
| MS | Roger Wicker | GOP | No | Wicker won a special election in 2008 after Trent Lott resigned mid-term |
| NE | Ben Nelson | Dem | Yes | Both parties hate him and he was likely to lose anyway |
| NM | Jeff Bingaman | Dem | Yes | He could have won but chose to retire |
| NV | Dean Heller | GOP | No | Heller was appointed when his predecessor was caught having an affair with a staffer's wife |
| NY | Kirsten Gillibrand | Dem | No | Appointed after Hillary Clinton resigned and won a special election in 2010 |
| ND | Kent Conrad | Dem | Yes | North Dakota is tough for a Democrat, but he has won before |
| TX | Kay Hutchison | GOP | Yes | She was embarrassed by her gubernatorial defeat |
| VA | Jim Webb | Dem | Yes | He apparently had enough of politics |
| WV | Joe Manchin | Dem | No | Won a special election in 2010 after Robert Byrd died |
| WI | Herb Kohl | Dem | Yes | Age probably played the biggest role here |
| WY | John Barrasso | GOP | No | He won a special election in 2008 after being appointed to fill a vacancy |