A small animal model that reproduces human immunodeficiency virus type 1 (HIV-1) pathogenesis may allow modeling of new therapeutic strategies in ways not approachable in mononuclear cell culture. We find that, as in humans, combination antiretroviral therapy (ART) in humanized (hu-) Rag2^−/−γ_c^−/− mice allows suppression of viremia below the limits of detection and recovery of CD4⁺ cells, while interruption of ART results in viral rebound and renewed loss of CD4⁺ T cells. Failure of ART in infected mice is associated with the appearance of drug resistance mutations. The hu-Rag2^−/−γ_c^−/− mouse may therefore facilitate testing of novel approaches to HIV replication and persistence.