Differences in HIV-1 gp120 sequence variation were examined in North American volunteers who became infected during a phase III vaccine trial using the rgp120 vaccine. Molecular adaptation of the virus in vaccine and placebo recipients from different ethnic subgroups was compared by estimating the dN/dS ratios in viruses sampled from each individual using three different methods. ANOVA analyses detected significant differences in d(N)/d(S) ratios among races (P < 0.02). gp120 sequences from the black individuals showed higher mean d(N)/d(S) ratios for all estimators (1.24-1.45) than in other races (0.66-1.35), and several pairwise comparisons involving blacks remained significant (P < 0.05) after correction for multiple tests. In addition, black-placebo individuals showed significantly (P < 0.02) higher mean d(N)/d(S) ratios (1.3-1.66) than placebo individuals from the other races (0.65-1.56). These results suggest intrinsic differences among races in immune response and highlight the need for including multiple ethnicities in the design of future HIV-1 vaccine studies and trials.