Recent studies of human immunodeficiency virus (HIV)-specific CD8⁺ T cells have focused on responses to single, usually HLA-A2-restricted epitopes as surrogate measures of the overall response to HIV. However, the assumption that a response to one epitope is representative of the total response is unconfirmed. Here we assess epitope immunodominance and HIV-specific CD8⁺ T-cell response complexity using cytokine flow cytometry to examine CD8⁺ T-cell responses in 11 HLA-A2⁺HIV⁺ individuals. Initial studies demonstrated that only 4 of 11 patients recognized the putative immunodominant HLA-A2-restricted p17 epitope SLYNTVATL, suggesting that the remaining subjects might lack significant HIV-specific CD8⁺ T-cell responses. However, five of six SLYNTVATL nonresponders recognized other HIV epitopes, and two of four SLYNTVATL responders had greater responses to HIV peptides restricted by other class I alleles. In several individuals, no HLA-A2-restricted epitopes were recognized, but CD8⁺ T-cell responses were detected to epitopes restricted by other HLA class I alleles. These data indicate that an individual's overall CD8⁺ T-cell response to HIV is not adequately represented by the response to a single epitope and that individual major histocompatibility complex class I alleles do not predict an immunodominant response restricted by that allele. Accurate quantification of total HIV-specific CD8⁺ T-cell responses will require assessment of the response to all possible epitopes.