Anergy is almost universal among patients with the acquired immunodeficiency syndrome (AIDS). To determine the prevalence and correlates of anergy in a population at risk for AIDS, we performed skin tests in 1120 gay men who were enrolled in a prospective study of the natural history of human immunodeficiency virus (HIV) infection. Anergy, defined as no induration to any of four intradermal antigens, was present in 12%. Individually, no induration was detected in response to tetanus toxoid (41%), mumps (28%), candida (47%), and trichophyton (72%). Anergy was strongly associated with the presence of antibody to HIV and with a reduced number of T helper lymphocytes, but not independently with generalized lymphadenopathy, the number of reported male sexual partners in the previous 2 years, the number of T suppressor lymphocytes, or with high titers of antibodies to cytomegalovirus. Nine percent of HIV antibody-negative subjects and 20% of antibody-positive subjects were anergic; anergy is not specific for serologically documented HIV infection in this population. Skin testing with only tetanus toxoid, candida, and mumps antigens may be sufficient to detect anergy. In the presence of HIV antibody, the ability of anergy to predict progressive immunodeficiency remains to be determined.