Background Previous studies have shown that health-related quality of life (HRQL) predicts survival in patients infected with human immunodeficiency virus (HIV). However, these studies predated the highly active antiretroviral therapy (HAART) era, included only a few patients receiving HAART, or had a limited duration of follow-up. This study investigates whether HRQL predicts survival among HIV-infected patients receiving HAART. Methods HIV-infected patients participating in the focus group of the AIDS Therapy Evaluation in the Netherlands (ATHENA) study and starting or already receiving HAART completed the Medical Outcomes Study HIV Health Survey at study entry (1 May 1998 through 31 December 2000). The physical health summary (PHS) and mental health summary (MHS) scores were calculated. All-cause mortality was established at 31 March 2008. Kaplan-Meier analysis and Cox regression models were performed to predict survival. Results The median follow-up was 8.4 years. Sixty-six patients (11.8%) died during follow-up. We found a significant relation between quartiles of PHS and survival ( P <.001 , log-rank test). Of patients with a PHS, 26 (20%) died in quartile 1 (indicating worst HRQL), 17 (13%) died in quartile 2, 10 (8%) died in quartile 3, and 5 (4%) died in quartile 4 (indicating best HRQL) ( P <.001 ). The prediction of PHS on survival was independent of other (clinical) parameters ( P <.001). No relation was found between MHS and survival ( P = .13). Conclusion Patient-reported HRQL predicted survival among HIV-infected patients receiving HAART. This information could be highly useful for physicians in determining the prognosis of their patients.