In this study, the immunogenicity of a recombinant pre-S2 containing hepatitis B vaccine was determined in a cohort of 147 homosexual men. Both seroconversion rate and geometric mean titers indicated that pre-S2 was less immunogenic than HBsAg. Forty-eight subjects, including nine non-responders and seven high-responders to HBsAg, were tested for HLA Class I and II antigens to study a possible association between HLA-type and non-response. Both HLA-B8 and HLA-DR3 were clearly overrepresented in non-responders to HBsAg. Non-response to pre-S2, observed in 7/9 non responders and 6/39 responders to HBsAg, was not associated with any of the tested HLA markers.