Background: Co-trimoxazole, a fixed-dose combination of two antimicrobial drugs offers a synergistic effect with a broad spectrum of antimicrobial action. Adherence to cotrimoxazole preventive therapy has been found to reduce the incidence of opportunistic infections and other AIDS-related illnesses. Cotrimoxazole preventive therapy is self-administered, and therefore, adherence cannot be insured, and the adherence has been low and opportunistic infections continue to be the major cause of mortality and morbidity in HIV, accounting for 47% of AIDS-related deaths. This study aimed to assess adherence and factors associated with cotrimoxazole preventive therapy (CPT) among adult human immunodeficiency virus (HIV) patients attending antiretroviral clinics in Jijiga hospitals.    Methods: Institutional-based-cross-sectional study was conducted from November to December, 2021 among 422 randomly selected adult HIV-positive patients attending Jijiga hospital. The collected data was entered into EPI-data version 3.1 and exported to SPSS version 24 for analysis. Binary and multivariable logistic regressions were used to identify factors associated with CPT adherence. Results 417 patients with HIV participated in the study with an overall adherence of CPT of 76.3% with 95% confidence interval (CI): 72.4%-81.3%; level of education-can read and write (AOR= 1.50 , 95% CI: 1.39 -2.73), taking substance (AOR= 1.88, 95% CI: 1.22–2.93), distance of the health facility greater than 5km (AOR= 1.79, 95% CI: 1.07-2.98), residence being rural (AOR =1.90, 95% CI: 1.14-3.17) not receiving counseling at refill (AOR= 1.33, 95% CI: 1.13-2.80), duration of ART less than 6 years and not disclosing HIV status to other family members (AOR =5.40, 95% CI: 3.42-8.14, and 3.30, 95% CI: 2.12-5.41 respectively) were significantly associated with magnitude of CPT.    Conclusions: To improve the adherence, continuous education and counselling, giving group service support for clients and patients having trends to disclose HIV status to other members of the family are some of the possible solutions.