ABSTRACT:Background: Human Immunodeficiency Virus (HIV) that causes HIV infection and Acquired Immunodeficiency Syndrome (AIDS) remains a significant global public health challenge in world history. Nonadherence promotes the development of drug resistance and treatment failure in individuals infected with the Human Immunodeficiency Virus. Objectives: To assess the determinants of nonadherence to the antiretroviral drug among people living with HIV in Ondo State, South-West, Nigeria. Methods: A correlation research design was utilized, and respondents were systematically sampled during either their clinical visits or visit to collect ARV drugs at the HAART clinic of General hospital Iju /Itaogbolu, Akure North, Ondo State. A 20-item Self-report questionnaire was used as an instrument of data collection. The questionnaire is divided into three (3) sections. Section A: Contains 8 items on sociodemographic data of the respondents, such as age, gender, ethnicity, religion, marital status, family type, educational level, and employment status. Section B: contains 6 questions as contained in the Simplified Medication Adherence Questionnaire (SMAQ). Section C: Entails the determinants of nonadherence to antiretroviral drugs. It contains 6 items. Data retrieved were analyzed using both descriptive and inferential statistics with a p-value set at 0.05. Results: We observed an above-average adherence rate of 59.8% and a nonadherence rate of 40.2%, respectively. The study also revealed that long waiting time, fear of stigmatization, family support, support from society, and experience of being treated differently because of HIV status were identified as determinants of nonadherence to antiretroviral drugs, with p-values ? 0.05 respectively. Conclusions: The study concluded that nonadherence to the antiretroviral drug needs to be tackled headlong to alleviate concerns of drug resistance and the resultant financial burden on the health systems from the need to control resistant strains of HIV and total treatment failure with increased morbidity and mortality. Health care professionals must improve their effort in counselling at initiation and during follow-up hospital visits.