Five hundred ninety-two drug users (IDUs) from community settings in San Francisco and Oakland, California, were screened for tuberculosis using the tuberculin skin test, as well as for skin test anergy using two controls: mumps antigen and either tetanus toxoid or Candida. Those nonresponsive to one skin test were more likely to be nonresponsive to another, even after stratifying by HIV status. Skin test anergy (defined as nonresponse to the tuberculin skin test and to both controls) occurred in 37% of HIV-positive and 11% of HIV-negative IDUs (p<0.001). Among HIV-negative IDUs, anergy was associated with city of residence (p<0.001), use of cocaine by any route in the last 30 days (p=0.026) and use of speedballs (heroin and cocaine) by any route in the last 30 days (p=0.053). Skin test anergy in this population of IDUs may reflect more generalized defects in the delayed hypersensitivity response. Other exposures besides HIV which occur in IDUs may result in impaired cellular immunity.