Adherence to anti-retroviral therapy (ART) regimen is essential for successful treatment and sustained viral control. Optimal adherence is the compliance to ART that achieves a sustained plasma drug concentration that suppresses viral replication. The objective of this study is to assess ART adherence and its determinants at Agaro Health Center ART Clinic, South Western Ethiopia. Facility-based cross sectional study was conducted from June 9-29, 2011. Patients were interviewed to collect adherence related information by using pretested semi-structured questionnaire. Subsequent charts of prescribed medications were reviewed using a pretested data collection format. A total of 209 respondents were included in the study, of which 127 (60.8%) were females and 82 (39.2%) were males. The average adherence rate was 98.1% among males and 99.5% among females. The overall average adherence rate among the respondents was 98.8%. One hundred sixty one (77.0%) respondents had a 100% adherence rate, 15 (7.2%) patients had a 93.3% adherence rate and the remaining 33 (15.8%) patients had adherence rate between 95 and 98% on average. The common reasons for missing of the prescribed doses were forgetting 27 (39.7%), being too busy 20 (29.4%), away from home 17 (25.0%) and being extremely ill 4 (5.9%). Of all the variables, sex, living alone, monthly income, use of stimulants and medications in addition to ART were significantly associated with non-adherence. The adherence rate among the study participants was found to be optimal, and near perfect adherence need to be maintained to obtain the optimum therapeutic outcome.