Immune control of human immunodeficiency virus type 1 (HIV) infection is typically associated with effective Gag-specific CD8+ T-cell responses. We here focus on HLA-B14, which protects against HIV disease progression, but the immunodominant HLA-B14-restricted anti-HIV response is Env specific (ERYLKDQQL, HLA-B14-EL9). A subdominant HLA-B14-restricted response targets Gag (DRYFKTLRA, HLA-B14-DA9). Using HLA-B14/peptide-saporin-conjugated tetramers, we show that HLA-B14-EL9 is substantially more potent at inhibiting viral replication than HLA-B14-DA9. HLA-B14-EL9 also has significantly higher functional avidity (P < 0.0001) and drives stronger selection pressure on the virus than HLA-B14-DA9. However, these differences were HLA-B14 subtype specific, applying only to HLA-B14:02 and not to HLA-B14:01. Furthermore, the HLA-B14-associated protection against HIV disease progression is significantly greater for HLA-B14:02 than for HLA-B14:01, consistent with the superior antiviral efficacy of the HLA-B14-EL9 response. Thus, although Gag-specific CD8+ T-cell responses may usually have greater anti-HIV efficacy, factors independent of protein specificity, including functional avidity of individual responses, are also critically important to immune control of HIV.IMPORTANCE In HIV infection, although cytotoxic T lymphocytes (CTL) play a potentially critical role in eradication of viral reservoirs, the features that constitute an effective response remain poorly defined. We focus on HLA-B14, unique among HLAs associated with control of HIV in that the dominant CTL response is Env specific, not Gag specific. We demonstrate that Env-specific HLA-B14-restricted activity is substantially more efficacious than the subdominant HLA-B14-restricted Gag response. Env immunodominance over Gag and strong Env-mediated selection pressure on HIV are observed only in subjects expressing HLA-B14:02, and not HLA-B14:01. This reflects the increased functional avidity of the Env response over Gag, substantially more marked for HLA-B14:02. Finally, we show that HLA-B14:02 is significantly more strongly associated with viremic control than HLA-B*14:01. These findings indicate that, although Gag-specific CTL may usually have greater anti-HIV efficacy than Env responses, factors independent of protein specificity, including functional avidity, may carry greater weight in mediating effective control of HIV.