Background. Depression is consistently associated with increased risk of Human Immunodeficiency Virus infection and poor antiretroviral treatment adherence. Though many factors have been reported as determinant factors of depression, site-specific evidence is needed to identify factors associated with depression among adults on antiretroviral treatment. Methods. An institution based cross-sectional study was carried out from March to May 2015 among 411 adults HIV/AIDS patients on ART clinic follow-up. Participants were selected using systematic random sampling techniques. Data were collected using chart review and interviewer- administered techniques. Both bivariable and multivariable logistic regressions were used to compute the statistical test associations by SPSS version-20. Variables with p value < 0.05 were considered as statistically significant. Results. Four hundred eleven patients with a mean age ± Standard Deviation of 36.1±9.2 years and with a total response rate of 97.6% were enrolled in the study. The prevalence of depression was 14.6% (95% CI, 10.90-18.2). Factors independently associated with depression were nonadherence to ART, eating two meals per day or less, having side effect of ART medication, being in the WHO Stage II or above of HIV/AIDS, and living alone with AOR (95% CI) of 3.3 (1.436, 7.759), 2.8 (1.382, 5.794), 4.7 (1.317, 16.514), 2.8 (0.142, 0.786), and 2.4 (1.097, 5.429), respectively. Conclusion. Though the magnitude of depression was found relatively low, it was commonly observed as a mental health problem among adult patients with HIV/AIDS on ART. Programs on counseling and close follow-up of adherence to ART, drug side effects, and nutrition should be strengthened. Health facilities should link adult patients with HIV/AIDS who live alone to governmental and nongovernmental social supporter organizations.