The cytosine deaminase APOBEC3G has been identified as a host factor that inhibits HIV-1 replication. We investigated whether genetic variants of APOBEC3G that could potentially affect the protein's expression or function were associated with the risk of infection in 122 Caucasians highly exposed to HIV-1. A novel C40693T variant was significantly associated with an increased risk of infection, suggesting that there might be a role for APOBEC3G in susceptibility to HIV-1 infection that warrants further investigation.