Background. Although efforts have been made to reduce AIDS-related mortality by providing antiretroviral therapy (ART) services, still people are dying while they are on treatment due to several factors. This study aimed to investigate the predictors of mortality among adult antiretroviral therapy (ART) users in Goba Hospital, Southeast Ethiopia. Methods. The medical records of 2036 ART users who enrolled at Goba Hospital between 2007 and 2012 were reviewed and sociodemographic, clinical, and ART-related data were collected. Multivariable Cox proportional hazards regression model was used to measure risk of death and identify the independent predictors of mortality. Results. The overall mortality incidence rate was 20.3 deaths per 1000 person-years. Male, bedridden, overweight/obese, and HIV clients infected with TB and other infectious diseases had higher odds of death compared with their respective counterparts. On the other hand, ART clients with primary and secondary educational level and early and less advanced WHO clinical stage had lower odds of death compared to their counterparts. Conclusion. The overall mortality incidence rate was high and majority of the death had occurred in the first year of ART initiation. Intensifying and strengthening early ART initiation, improving nutritional status, prevention and control of TB, and other opportunistic infections are recommended interventions.