Background: A complex and negatively reinforcing relationship exists between infection with Human Immune Deficiency Virus (HIV) and malnutrition. HIV-induced immune impairment and its resulting opportunistic infections (OIs) can lead to malnutrition and nutritional deficits, can, in turn, hasten the progression of HIV infection and reduce chances of survival. The determinants of undernutrition among patients receiving antiretroviral therapy (ART) is poorly understood in Ethiopia, despite a high prevalence of food-insecurity that overlaps with a generalized HIV/AIDS epidemic. Therefore, this study aimed to assess determinants of undernutrition among adult patients receiving antiretroviral therapy at Debre Markos Referral Hospital in Northwest Ethiopia. Methods: We conducted an institution-based, unmatched, case-control study with 636 adult patients receiving antiretroviral therapy. We randomly selected 212 patients with poor nutritional outcomes (cases) and 424 without undernutrition (controls) and then conducted a chart review to collect information on their treatment, socio-economic, and demographic background. Data were analyzed using bivariable and multivariable logistic regression to identify factors associated with under nutrition. Results: We found that greater age (AOR = 1.02, 95% CI: 1.01,1.05), fair or poor adherence (AOR = 2.77, 95% CI: 1.40, 5.50 and AOR = 4.72, 95% CI: 1.92, 11.6), and the presence of OIs (AOR = 1.70, 95% CI: 1.12, 2.52), anemia (AOR = 1.81, 95% CI: 1.07, 3.07), or eating problems (AOR = 3.40, 95% CI: 2.27, 5.10), were all independently and positively associated with under nutrition. Starting treatment with a medium or low CD4 count was protective (AOR = 0.61, 95% CI: 0.39, 0.96 and AOR = 0.49, 95% CI: 0.27, 0.88). Having social support (AOR = 0.64, 95% CI: 0.43, 0.95), and having a source of informal care-giving (AOR = 0.48, 95% CI: 0.27, 0.84), reduced the odds of undernutrition. Conclusion: Our findings support calls for treating HIV infection early and aggressively, while closely monitoring patients for opportunistic infections that might affect eating and drug side effects that may affect appetite. The role of disclosure, peer-caregivers and age in preventing undernutrition should be explored in future research.