© 2019 The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: firstname.lastname@example.org. HLA-I-associated human immunodeficiency virus (HIV) adaptation is known to negatively affect disease progression and CD8 T-cell responses. We aimed to assess how HLA-I-associated adaptation affects HIV vaccine-induced CD8 T-cell responses in 2 past vaccine efficacy trials. We found that vaccine-encoded adapted epitopes were less immunogenic than vaccine-encoded nonadapted epitopes, and adapted epitope-specific responses were less polyfunctional than nonadapted epitope-specific responses. Along those lines, vaccine recipients with higher HLA-I adaptation to the Gag vaccine insert mounted less polyfunctional CD8 T-cell responses at the protein level. Breadth of response, which correlated with viral control in recipients who became infected, is also dampened by HLA-I adaptation. These findings suggest that HLA-I-associated adaptation is an important consideration for strategies aiming to induce robust CD8 T-cell responses.