OBJECTIVE: To estimate early and long-term mortality and associated risk factors in adults receiving highly active antiretroviral therapy (HAART) in Thailand. DESIGN: Prospective observational cohort. METHODS: Previously untreated adults starting HAART in 2002-2009 were followed in 43 public hospitals. Kaplan-Meier probability of survival was estimated up to 5 years of therapy. Factors associated with early (≤6 months) and long-term (>6 months) mortality were assessed using Cox regression analyses. RESULTS: A total of 1578 adults received HAART, 74% women, median age 33 years, CD4 count 124 cells/mL, median follow-up was 50 months (IQR 41-66). Eighty-nine (6%) patients died (37 occurred ≤6 months and 52 >6 months) and 183 (12%) were lost to follow-up. Probability of survival (95%CI) was 97.5% (96.7-98.2) at 6 months; 96.6% (95.6-97.4) at 1 year and 93.5% (91.9-94.8%) at 5 years. Probability of being alive and on follow-up was 80.8% (78.5-82.8) at 5 years.Early mortality was associated with anemia (aHR 3.6, 95%CI 1.7-7.5) and low CD4 (aHR 1.6, 95%CI 1.1-2.2, per 50 cells decrease) at treatment initiation. Long-term mortality was associated with persistent anemia (aHR, 4.9; 95%CI 2.1-11.6); CD4 increase from baseline <50cells/mm (aHR 3.1; 95%CI 1.6-5.7) and viral load >1000 copies/mL (aHR 2.8; 95%CI 1.3-6.1) at 6 months of HAART; male gender and calendar year of enrollment. CONCLUSION: Early mortality was associated with anemia and severe immunosuppression at initiation of therapy. Long-term mortality was associated with persistent anemia, CD4 and virologic response at 6 months of therapy over baseline characteristics, highlighting the importance of laboratory monitoring.