Immunosuppression induced by the human immunodeficiency virus (HIV-1) increases the risk of death. We measured the influence of immunological and virological factors and the type of highly active anti-retroviral therapy (HAART) on this risk. Adaptive (lymphocyte) and innate (natural killer) immune correlates and maximum HIV viral loads were assessed for association with mortality using univariate and multivariate analyses. The protective effect of HAART regimens, containing protease inhibitors (PI) and/or non-nucleoside reverse transcriptase inhibitors (NNRTI) on mortality were also examined in a prospectively recorded cohort of 9621 HIV-infected individuals. From this entire cohort, 5873 HIV infected individuals (61%) have been followed-up in the HAART era and of these 499 (8·5%) have died. In multivariate analyses, CD4 counts below the 50th centile and CD8 and CD19 counts below the 25th centile were significantly associated with mortality, as was increased age (P < 0·001). Innate immune subset levels had no effect on mortality. A maximum HIV viral load greater than the 75th centile was also associated independently with mortality (P < 0·035). Exposure to either a PI or an NNRTI-containing HAART regimen, or both together, was protective against death compared with no anti-retrovirals (P < 0·001). Effective HAART-induced maintenance of the adaptive immune system (CD4, CD8 and CD19 counts) protects from HIV-related mortality.