PIP: Speculation has existed for decades on the association between the lack of male circumcision and the sexual transmission of disease. It has been suggested that the surface epithelium of the glans develops a protective keratin layer following circumcision which functions like a natural condom against contracting disease. Circumcised males may therefore be less susceptible to contracting sexually transmitted diseases (STD), including HIV. The identification of simian immunodeficiency virus-infected mononuclear cells in the dermis and epidermis of the penile foreskin of macaques also suggests that male circumcision may reduce the infectivity of men with HIV. The authors review the evidence in support of the association between the lack of circumcision and STDs, and the possible biological explanations. They also discuss the implications for public health interventions and suggest areas and methods for further research. Twenty-three published study reports linking circumcision status to HIV infection are identified and include retrospective studies including partner studies, cross-sectional serosurveys, a longitudinal study, and ecological correlations. Five studies linked the lack of circumcision to STDs other than HIV infection. In interpreting the data, the authors consider susceptibility versus infectivity, assessment of behaviors and adjustment for confounding, selection bias, misclassification of exposure, measure of association, and publication bias. It is ultimately concluded that more studies are needed to quantify the relative risk associated with the lack of male circumcision. Observational designs could be employed to that end along with laboratory and primate research.