Background: Onchocerciasis is an infection of a filarial worm which is endemic in Sub-Saharan Africa, including Ethiopia. Annual mass treatment with high coverage over for a long period of time should lead to a complete interruption of transmission and the ultimate elimination of the parasite. However, in Ethiopia, the required coverage levels were not achieved. Thus, the aim of this study was to identify the possible determinants of onchocerciasis treatment adherence in Assossa District. Methods: A case-control study was conducted among 528 respondents (176 cases and 352 controls). Cases were respondents who took all five doses of treatments, and controls were those who took at most four does of ivermectin treatments (missed at least one or more doses). Structured questionnaire was used for data collection. Each possible factor for treatment adherence, with a P value < 0.2 obtained in the bi-variable logistic regression was entered into the multivariable logistic regression models to control the confounding factors. p value < 0.05 was used as cutoff point for a variable to become a significant determinant of treatment adherence in multivariable logistic regression. Results: Participation in selecting drug distributers [AOR = 2.7, 95%CI (1.7-4.1)], measuring height for dose determination [AOR = 3.6, 95%CI (1.9-6.7)], perceived risk of getting onchocerciasis [AOR = 2.1, 95%CI (1.6-2.7)], living near running water [AOR = 1.7, 95%CI (1.1-2.8)], and perceived needs of support for intake of ivermectin [AOR = 3.2, 95%CI(2.1-4.9)] were independent predictors for t treatment adherence. Conclusions: Treatment adherence was influenced by participation in selecting drug distributers, measuring height for dose determination, perceived risk of getting onchocerciasis, living near running water and perceived needs of support for intake of ivermectin. To improve intake of the drug and its adherence, the community should be empowered to make decisions, and counseling family members and sensitizing those living far from river sides is commendable. Health information about onchocerciasis should be strengthening to increase risk perception.