OBJECTIVE To observe the long term response to first-line antiretroviral therapy (ART) in HIV and hepatitis B virus (HBV) co-infected patients in Ghana and explore predictors of poor clinical outcomes. METHODS Retrospective cohort study of hepatitis B surface antigen (HBsAg) positive and negative patients receiving predominantly NNRTI-based ART with lamivudine plus either zidovudine or stavudine for up to seven years. Cox proportional hazards and Kaplan Meier survival analyses compared clinical outcomes and identified baseline characteristics predictive of poor outcomes. A mixed effects model compared changes in CD4 counts. RESULTS A total of 299 HBsAg-positive and 1869 HBsAg-negative patients started ART between 2004 and 2008. Over a median 35 months of follow-up, HBsAg-positive patients were more likely to die or default care than HBsAg-negative patients, aHR 1.36 (95% CI, 1.03-1.80). HBsAg-positive patients were also more likely to develop Grade 3/4 hepatotoxicity than HBsAg-negative patients, HR 1.99 (1.16-3.40) on survival analysis. There was no significant difference in CD4 responses between HBsAg-positive and HBsAg-negative patients. CONCLUSIONS HBsAg-positive patients are at significantly increased risk of adverse clinical outcomes after starting ART. Further studies are warranted to evaluate whether these risks remain now that tenofovir is becoming routinely available in Ghana.