Cognitive deficits are a significant clinical problem associated with HIV infection. Although the role of CCR5 in immunity and in HIV infection has been studied widely, its role in neuronal plasticity, learning and memory, and in HIV-associated cognitive deficits is not well understood. In a reverse genetic screen, we found that a Ccr5 null mutation results in hippocampus-dependent memory enhancements. Molecular and cellular studies indicated that the memory enhancement is caused by increases in MAPK/CREB signaling and enhanced long-term potentiation (LTP). Ccr5 knockdown in the hippocampus of adult mice also led to enhancements in hippocampal memory, thus confirming a role for this receptor in adult plasticity and memory. These results suggest that besides its role as a co-receptor for HIV, CCR5 is a powerful suppressor for learning and memory, and that CCR5 over-activation by viral peptides may contribute to HIV-associated cognitive deficits. Consistent with this hypothesis, the HIV V3 loop peptide, known to bind and activate CCR5, caused deficits both in signaling implicated in learning and memory (hippocampal MAPK activation) and in a key cellular mechanism for learning and memory (LTP). Accordingly, acute hippocampal injection of V3 peptide also caused memory deficits. Importantly, V3 peptide induced signaling, LTP and memory deficits were prevented by a Ccr5 knockout. Overall, our results demonstrate that CCR5 plays an important role in plasticity and memory, and CCR5 over-activation may contribute to the cognitive deficits caused by HIV coat proteins.