Circumcised men have a lower risk of HIV-1 infection than uncircumcised men. Laboratory findings suggest that the foreskin is enriched with HIV-1 target cells. However, some data suggest that circumcision could simply be a marker for low-risk behaviours. In a prospective study of 2298 HIV-uninfected men attending sexually transmitted infection clinics in India, we noted that circumcision was strongly protective against HIV-1 infection (adjusted relative risk 0.15; 95% CI 0.04-0.62; p=0.0089); however, we noted no protective effect against herpes simplex virus type 2, syphilis, or gonorrhoea. The specificity of this relation suggests a biological rather than behavioural explanation for the protective effect of male circumcision against HIV-1.