Background: The number of annual acquired immune deficiency syndrome (AIDS)-related deaths worldwide is steadily decreasing. In resource-poor settings, like Ethiopia the treatment was started recently. The survival and factors contributing to mortality are not yet well established. Objective: To analyze the survival and predictors of mortality among adult patients started highly active antiretroviral treatment from September, 2005 to August, 2010 at Debre Markos Hospital, Ethiopia. Methods: This was a retrospective cohort study among 930 adults who started HAART between September 2005 and August 2010 at Debre-Markos Hospital. Data was extracted from paper based medical records data base and the survival of patients was estimated by Kaplan-Meier Predictors of mortality were identified by Cox proportional hazards models. Results: The survival patients were 57.0% (95% CI [53-60] at 72 months. The significant predictors of mortality were advanced WHO stage (AHR=1.6, 95% CI [1.118-2.371]), mild anemia (AHR=2.6, 95% CI [1.886-3.640]), moderate to severe anemia (AHR=4.3, 95% CI [2.998-6.131]), poor adherence (AHR=3.1, 95% CI [2.341-4.129]), CD4 50-99 cells/l (AHR=2.0, 95% CI [1.058-3.889]), CD4<50 cells/l (AHR=2.2, 95% CI [1.140-4.182]) and not taking cotrimoxazole prophylaxis (AHR=1.7, 95% CI [1.272-2.172]). Conclusion: The study has shown an overall high mortality. The advanced WHO stage, anemia, not taking cotrimoxazole prophylaxis, poor adherence and low CD4 cell count plays an important role in the mortality of patients. A careful monitoring of patients particularly during the first 3 months of HAART is necessary.