Although human immunodeficiency virus-1 (HIV-1) infects quiescent and proliferating CD4⁺ lymphocytes, the virus replicates poorly in resting T cells^,,,,,. Factors that block viral replication in these cells might help to prolong the asymptomatic phase of HIV infection; however, the molecular mechanisms that control this process are not fully understood. Here we show that Murr1, a gene product known previously for its involvement in copper regulation^,, inhibits HIV-1 growth in unstimulated CD4⁺ T cells. This inhibition was mediated in part through its ability to inhibit basal and cytokine-stimulated nuclear factor (NF)-κB activity. Knockdown of Murr1 increased NF-κB activity and decreased IκB-α concentrations by facilitating phospho-IκB-α degradation by the proteasome. Murr1 was detected in CD4⁺ T cells, and RNA-mediated interference of Murr1 in primary resting CD4⁺ lymphocytes increased HIV-1 replication. Through its effects on the proteasome, Murr1 acts as a genetic restriction factor that inhibits HIV-1 replication in lymphocytes, which could contribute to the regulation of asymptomatic HIV infection and the progression of AIDS.