Highly active antiretroviral therapy (HAART) has been shown to be effective in different populations, but data among injection drug users are limited. Human immunodeficiency virus-infected injection drug users recruited into the Acquired Immunodeficiency Syndrome Link to Intravenous Experiences (ALIVE) Study as early as 1988 were tested semiannually to identify their first CD4-positive T-lymphocyte cell count below 200/microl; they were followed for mortality through 2002. Visits were categorized into the pre-HAART (before mid-1996) and the HAART eras and further categorized by HAART use. Survival analysis with staggered entry was used to evaluate the effect of HAART on acquired immunodeficiency syndrome-related mortality, adjusting for other medications and demographic, clinical, and behavioral factors. Among 665 participants, 258 died during 2,402 person-years of follow-up. Compared with survival in the pre-HAART era, survival in the HAART era was shown by multivariate analysis to be improved for both those who did and did not receive HAART (relative hazards = 0.06 and 0.33, respectively; p < 0.001). Inferences were unchanged after restricting analyses to data starting with 1993 and considerations of lead-time bias and human immunodeficiency viral load. The annual CD4-positive T-lymphocyte cell decline was less in untreated HAART-era participants than in pre-HAART-era participants (-10/microl vs. -37/microl, respectively), suggesting that changing indications for treatment may have contributed to improved survival and that analyses restricted to the HAART era probably underestimate HAART effectiveness.