The impact of human immunodeficiency virus (HIV) infection and other risk factors on mortality was studied in a cohort of Dutch injection drug users and drug users who did not inject. Participants were recruited between 1985 and 1992 and followed up through 1993. Vital status was ascertained through repeat visit information, supplemented by population register data. A total of 77 deaths were recorded among 632 drug users, for a mortality rate per 1,000 person-years of 7 for HIV-negative noninjection drug users, 18 for HIV-negative injection drug users, and 64 for HIV-positive injection drug users. In multivariate analyses, limited to injection drug users, a positive HIV serostatus, age above 40 years, and using benzodiazepines several times daily were significantly associated with an elevated risk of death, both for death from all causes and for death preceding acquired immunodeficiency syndrome (AIDS) diagnosis (pre-AIDS). For pre-AIDS death, the adjusted relative risk associated with HIV infection was 2.2 (95% confidence interval 1.3-3.7). Only 38% of HIV-infected injection drug users who died were diagnosed with AIDS. However, 76% of HIV-infected injection drug users who died without AIDS diagnosis had evidence of immunosuppression (CD4 count < 500/microliters). Daily use of methadone and participation in needle and syringe exchange schemes were not associated with lower mortality rates. This study illustrates in a group of injection drug users with a 30% HIV seroprevalence and a high background mortality the profound influence on mortality that HIV infection has gained.