BACKGROUND:: Although nearly 2 million people live with HIV in Latin America and the Caribbean, mortality rates after initiation of highly active antiretroviral therapy (HAART) have not been well described. METHODS:: Five thousand one hundred fifty-two HIV-infected, antiretroviral-naive adults from clinics in Argentina, Brazil, Chile, Haiti, Honduras, Mexico, and Peru starting HAART during 1996-2007 were included. First-year mortality rates and their association with demographics, regimen, baseline CD4, and clinical stage were assessed. RESULTS:: Overall 1-year mortality rate was 8.3% [95% confidence interval (CI): 7.6% to 9.1%], although variable across sites: 2.6%, 3.7%, 6.0%, 13.0%, 10.8%, 3.5%, and 9.8% for clinics in Argentina, Brazil, Chile, Haiti, Honduras, Mexico, and Peru, respectively. Eighty percent of deaths occurred within the first 6 months. Median baseline CD4 was 107 cells per milliliter, ranging from 79 (Peru) to 163 (Argentina). Mortality estimates adjusting for CD4 were similar across sites (1.1%-2.8% for CD4 = 200), except for Haiti, 7.5%, and Honduras, 7.0%. Death was associated with lower CD4 [adjusted hazard ratio for CD4 = 200 vs. CD4 = 50 was 0.58; 95% CI: 0.40 to 0.85] and clinical AIDS (hazard ratio = 3.1; 95% CI: 2.1 to 4.5). CONCLUSIONS:: Mortality rates were similar to those reported elsewhere for resource-limited settings. Disease stage at HAART initiation, treatment eligibility criteria, program age, and background mortality rates may explain some variability in prognosis between sites. Copyright © 2009 by Lippincott Williams & Wilkins.