To identify prognostic indicators of survival at different CD4+ cell levels, independent of highly active antiretroviral therapy (HAART), among injection drug users (IDUs). A community-recruited cohort of injection drug users followed semiannually from 1988 through 2000. Five partially overlapping subcohorts were defined by when participants first reached a CD4 cell level of 351 to 500, 201 to 350, 101 to 200, 51 to 100, or ≤50 cells/μL. Prognostic factors were measured at entry into each category. Kaplan-Meier survival estimates for HIV-related death and Cox regression models were constructed by CD4+ category. Among the 1030 HIV-infected IDUs, survival improved in the HAART-era with hazard ratios 0.42, 0.36, 0.24, 0.21, and 0.25, respectively, for CD4+ cell groups of 500 to 351, 350 to 201, 200 to 101, 100 to 51, and ≤50 cells/μL. Shorter survival was associated with prior hospitalization, AIDS, and sexually transmitted disease, with similar effects in the pre-HAART and HAART eras. For the lowest CD4+ cell level, prior sepsis or endocarditis, outpatient/emergency room visits, and alcohol use provide additional prognostic value. Survival among HIV-infected IDUs improved since the introduction of HAART, even though utilization of HAART was incomplete. Clinical and behavioral variables provided prognostic information about survival, including substance use indicators.