Introduction: Hypertension is a global challenge which accounts for high morbidity and mortality rates in the world. The availability of effective anti-hypertensive medications does not result in a good outcome in controlling blood pressure which points towards poor adherence. Thus, this study was conducted to assess the determinants of adherence to anti-hypertensive medication among hypertensive patients on follow-up in Hawassa Referral Hospital. Methods: Institution-based case-control study was conducted on a sample of 289 clients from February to May 2018. Census was conducted on 1600 clients to select cases and controls. Then, systematic random sampling was used to select study subjects, and adherence was measured by Morisky medication adherence scale. The associations of variables were analyzed using bivariable followed by multivariable logistic regression analyses. Results: The respondent's adherence to medication was found to be 67% as measured by Morisky medication adherence scale. The multivariate logistic regression analysis showed that medication adherence was found to be better in younger age (<45) (AOR ¼ 3.8), clients living in urban areas (AOR ¼ 6.84), those clients who had good knowledge (AOR ¼ 3.13), those with no co-morbidities (AOR ¼ 3.14) and patients who controlled their blood pressure (<140/90) (AOR ¼ 2.35). Conclusions: The rate of medication adherence was found to be low, and hence educational interventions focusing on factors promoting adherence and patients' health support should be implemented.