There is continuing interest in the longer term effects of highly active antiretroviral therapy (HAART) on the risk of cardiopulmonary events. We assessed this using updated administrative data from an open retrospective cohort of HIV-infected persons receiving care from the US Veterans Affairs (VA). Information on 41,213 HIV-infected patients receiving VA care between January 1993 and December 2003 was included. Patients were followed for an average of 4 years or 168,213 person-years of follow-up. The death rate fell from 20.9 deaths per 100 patient-years of observation in 1995 to 5.2 deaths per 100 patient-years in 2003. In patient-level analysis, adjusted hazard ratios for death dropped precipitously for all races to a low of 0.18 (95% confidence interval: 0.15 to 0.23) at 72 months of exposure to HAART. Hazards for serious cardiovascular events remained near 1.0 for exposure to HAART, and hazards for serious cardiovascular events, stroke, or death were only slightly higher than for death alone. No selection effects or secular trends were found. The benefits of HAART continued to increase in the 8 years after introduction and with 6 years of individual use. The risk of serious cardiovascular events should be factored into individual patient management but does not pose an important public health risk.