BACKGROUND The epitope specificities and antiviral activities of class I HLA-restricted CD8(+) T cells, especially those induced during human immunodeficiency virus type 1 (HIV-1) primary infection, are important considerations in designing HIV-1 vaccines. Conserved epitopes may be more commonly and persistently recognized than variable epitopes, as they may be more likely to be present in infecting viruses. However, some studies have shown preferential or similar targeting of variable versus conserved epitopes during primary infection. METHODS We analyzed cytotoxic T-lymphocyte (CTL) responses toward predefined conserved and variable epitopes in 45 subjects during primary (n = 34) and/or chronic infection (n = 16). RESULTS Conserved and variable CTL epitopes were recognized with similar probabilities, whereas conserved epitopes generally elicited subdominant responses during both primary and chronic infection. During primary infection, CTL responses against Gag versus responses against Env and variable epitopes tended to be associated with lower and higher viral loads, respectively. During chronic infection, Env-specific responses tended to be associated with lower CD4(+) cell counts. CONCLUSIONS Subdominant CTL recognition of conserved HIV-1 epitopes commonly occurs from the primary through chronic stages of HIV-1 infection. These findings underscore the challenge in designing T cell-based vaccines that can induce immunodominant CTL responses to conserved HIV-1 regions.