Epitope-specific CD8⁺ T lymphocytes may play an important role in controlling human immunodeficiency virus (HIV)/simian immunodeficiency virus replication. Unfortunately, standard cellular assays do not measure the antiviral efficacy (the ability to suppress virus replication) of CD8⁺ T lymphocytes. Certain epitope-specific CD8⁺ T lymphocytes may be better than others at suppressing viral replication. We compared the antiviral efficacy of two immunodominant CD8⁺ T lymphocyte responses—Tat_28-35SL8 and Gag_181-189CM9—by using a functional in vitro assay. Viral suppression by Tat-specific CD8⁺ T lymphocytes was consistently greater than that of Gag-specific CD8⁺ T lymphocytes. Such differences in antigen-specific CD8⁺-T-lymphocyte efficacy may be important for selecting CD8⁺ T lymphocyte epitopes for inclusion in future HIV vaccines.