Background: Fatigue is one of the most common and devastating HIV-related symptoms, with a varying prevalence in different study areas. In Ethiopia, there is a paucity of information on the magnitude and factors associated with fatigue among HIV/AIDS patients. This may lead to under-diagnosis and eventually under-management of the symptom. Objectives: This study assessed the prevalence and factors associated with fatigue among adults living with HIV/AIDS attending antiretroviral therapy at health facilities of Mekelle city, Tigray, North Ethiopia, 2019. Methods: Institution based cross-sectional study design was conducted among 609 HIV/AIDS patients who were selected by using a systematic random sampling method. Data were collected by using interviewer administered structured questionnaire. Level of fatigue was measured by Fatigue Severity Scale. Results: The prevalence of fatigue was found to be 51.7%. The factors associated with fatigue were: Parity [AOR= 2.01; 95% CI: 1.09-3.71], CD4 count 200-499 cells/mm3 [AOR= 2.81; 95% CI: 1.58-4.99], anemia [AOR= 4.90 95% CI: 2.40-9.97], co-morbidities [AOR= 3.65; 95% CI: 1.71-7.78], depression [AOR= 3.68 95% CI: 1.99-6.79], not being physically active [AOR= 3.20 95% CI: 1.50-6.81], clinical stage II or IV HIV [AOR= 3.11; 95% CI: 1.51-6.40] and [AOR= 4.08; 95% CI: 1.37-12.14], respectively. Conclusion: The finding of this study revealed that fatigue is a common health problem among adult PLHIV. Factors associated with fatigue included: Parity, CD4 count 200-499 cells/mm3, Clinical Stage II or IV HIV, anemia, co-morbidities, depression, and not being physically active. The health care service needs to address the predisposing factors by provision optimum care so that PLHIV can be encouraged in physical activity in order to relieve the impact of fatigue. Keywords: Fatigue, HIV/AIDS, Associated factors, Prevalence, Ethiopia