BACKGROUND: Treatment adherence is critical for the success of antiretroviral therapy (ART) for people living with HIV. There is limited representative information on ART drug adherence and its associated factors from Southern Ethiopia. We aimed at estimating the level of adherence to ART among people living with HIV and factors associated with it in 20 randomly selected ART clinics of Southern Ethiopia. METHODS: In this cross-sectional study, we interviewed consecutive HIV patients on first-line antiretroviral regimen attending the clinics in June 2014 using a pretested and structured questionnaire. For measuring adherence, we used 4-day recall method based on "The AIDS Clinical Trial Group adherence assessment tool". Patients were classified as "Incomplete adherence" if they missed any of the doses in the last 4 days. Data were singly entered using EpiData and descriptive analysis, and unadjusted odds ratios were calculated using EpiDataStat software. Multivariate logistic regression analysis was performed using Stata v12.0. RESULTS: Of 974 patients interviewed, 539 (56%) were females, and mean age was 35 years. The proportion of patients with incomplete adherence was 13% (95% confidence interval: 11%-15%). In multivariate analysis, factors significantly associated with incomplete adherence included young age, being Protestant Christian, consuming alcohol, being single, and being a member of an HIV association. Psychosocial factors like stigma, depression, and satisfaction to care were not associated with incomplete adherence in the current context. CONCLUSION: The overall adherence to ART was good. However, there were certain subgroups with incomplete adherence who need special attention. The health care providers (especially counselors) need to be aware of these subgroups and tailor their counseling to improve adherence among these groups. Exploratory qualitative studies may help uncover the exact reasons for incomplete adherence.