The provision of Antiretroviral Therapy (ART), HIV/AIDS is becoming a chronic manageable disease; therefore to manage chronic disease, adherence to HIV medication is very important but a variety of other factors may complicate ART adherence that needs devotion from patients, provisions of health services and health care professionals, and having social support from the society. The purpose of this study was to determine the level of adherence to ART and associated factors among adult antiretroviral drugs (ARV) users. A cross sectional study was carried out at Arba Minch Hospital from March 5 to May 5, 2015. One month patients’ self-report and pharmacy refill records were used to assess adherence. Data were collected by a standard questionnaire after pre-tested and data abstraction format. The collected data were entered in to Epi-Info and it was exported in to SPSS for data analysis. Multiple logistic regressions analysis was applied and statistical significance test was declared at P-value <0.05 and OR with 95% CI. Based on patients’ self-report dose adherence, among the 428 study participants, the magnitude of adherence to ART in a month before interview was 77.10%. Multivariable analysis showed that, adherence was positively associated with sex (male) (AOR=3.03, CI (1.69-5.42)), free from substance uses (AOR=3.49, CI (1.80-6.77)), absence of side effect of drugs (AOR =2.61, CI (1.19-5.73)), ART schedule fit to daily routines (AOR= 2.93, CI (1.24-6.91)) and feeling comfort on taking ART drug in front of others (AOR=3.32, CI (1.54-7.16)). The ART adherence rate of this study was relatively low compared with WHO standard and others study in Ethiopia. Sex, feeling comfort on taking the ART drugs, ART schedule fit to daily routines, substance use and drug side effects were strong predictors of adherence.