Recent cases of "AIDS-like" CD4 lymphocytopenia in the absence of HIV infection have generated considerable scientific and public interest. We studied CD4 cell counts and percentages from 1984 to 1992 among 1,246 HIV-seronegative injecting drug users in New York City, a population at very high risk for exposure to bloodborne pathogens. Severe CD4 lymphocytopenia was rare, and there was no evidence of an increase over time. Of 229 subjects with longitudinal data, only four met the surveillance definition for "idiopathic CD4 lymphocytopenia" (ICL). CD4 cell counts of < 500 cells/microliters were, however, associated with subsequent HIV seroconversion (12.7/100 person-years at risk, relative risk (RR) = 4.53, 95% exact binomial confidence interval (CI) 1.7-10.7, p = 0.002).