OBJECTIVE To describe the causes of mortality among the HIV-infected in southern India in the era of highly active antiretroviral therapy (HAART). METHODS Analyses of this patient cohort were conducted using the YRG Centre for AIDS Research and Education HIV Natural History Observational Database. Causes of death were then individually confirmed by patient chart review. RESULTS Sixty-nine deaths occurred within the inpatient unit; 25% were female and the median age of the 69 patients was 34 years. Over half of the patients (55%) died within three months of initiating HAART. At the time of enrollment into clinical care, the median CD4 cell count was 64 cells/microl (interquartile range (IQR) 37-134). At the time of initiating HAART, the median CD4 cell count was 58 cells/microl (IQR 31-67) for patients who died within 3 months of initiating HAART and 110 cells/microl (IQR 77-189) for patients who died more than 3 months after initiating HAART. Close to three-fourths of patients (70%) died from an AIDS-defining illness (ADI). The major ADI causes of death included Pneumocystis jiroveci pneumonia (22%), extrapulmonary tuberculosis (19%), CNS toxoplasmosis (12%), and pulmonary tuberculosis (10%). A tenth of patients died from cerebrovascular infarcts. Three patients (4%) died from non-Hodgkin lymphoma. CONCLUSIONS AIDS-related events continue to be the major source of mortality among the HIV-infected in southern India in the era of HAART. This mortality pattern justifies increased proactive efforts to identify HIV-infected patients and initiate HAART earlier, before patients present to care with advanced immunodeficiency.