Republican state Sen. Robert Hurt carried the Charlottesville-based seat.
The district leans Republican — John McCain carried it in 2008 — but Perriello supported the Democratic majority on key legislation, including the healthcare overhaul and the economic stimulus. Obama singled Perriello out often for doing what was right, even though it wasn't politically popular.
Other Democrats in closely-watched Virginia races also trailed.
Rick Boucher, a 14-term incumbent who ran unopposed in 2008, was another casualty of the Republican wave. State Delegate Morgan Griffith won the 9th District seat in the western part of the state.
Glenn Nye, elected with Perriello in 2008, also appeared headed to defeat despite votes against his party on health reform and cap and trade.
Virginia was another red state carried by Obama in 2008. The state's former governor, Tim Kaine, is the chairman of the Democratic National Committee.