Background: Fatigue is one of the most common bothersome HIV-related morbidity. The HIV prevalence in Ethiopia is heterogeneous by sex, geographic areas, and population groups. In Ethiopia, there is a need to estimate the burden of fatigue among HIV/Acquired Immune Deficiency Syndrome (AIDS) adults to gain regional insight into this disabling symptom.Method: An institutional-based cross-sectional study was conducted among 392 HIV/AIDS patients attending an antiretroviral therapy clinic at the University of Gondar Hospital, Ethiopia using a systematic random sampling technique. Data were collected using a structured questionnaire, nine-item version Fatigue Severity Scale (FSS), and PHQ-9 (Patients Health Questionnaire 9). Logistic regression model was used to identify factors associated with the reported presence of fatigue.Result: The mean age of the participants was 40.5 ± 8.5 years. The prevalence of HIV-related fatigue was 53.3% and about 66% of HIV-infected women experienced fatigue. The factors associated with fatigue experience were; female gender (AOR: 0.196, 95%CI; 0.05, 0.92), being married (AOR: 0.13, 95% CI 0.23, 0.7), low income (AOR: 12.3, 95% CI 2.5, 60.15), unemployed (AOR: 3.9, 95%CI (1.02, 14.739), parity (AOR: 7.99, 95% CI 1.66, 38.41), being anemia (AOR: 13.34, 95% CI 2.74, 65.01), mild weight loss (AOR: 4.9 95% CI 4.33, 19.5) and moderate weight loss (AOR: 5.5 95% CI 3.11, 21.3), respectively.Conclusion: The findings of this study revealed that experiencing fatigue is quite high among adults living with HIV. It is important for health care professionals and people living with HIV to understand; the possible causes of fatigue, remedies, and ways to reclaim energy. The predisposing factors and complications that cause fatigue should be aggressively diagnosed and treated by the clinicians.