BACKGROUND: Anti Retroviral Therapy (ART) is the cornerstone for comprehensive health sector response to Human Immunodeficiency Virus (HIV) treatment, care and support. Adherence of at least 95% is needed to keep HIV under control, as per World Health Organization (WHO) guidelines. This study was aimed at identifying the overall adherence level of, and barriers and facilitators to adherence for patients taking ART in different clinics in all five development regions of Nepal. METHODS: A descriptive cross-sectional study was conducted among ART clients receiving free ART from Government of Nepal ART clinics. A total of 435 clients taking ART from twelve ART clinics in different regions of Nepal, aged fifteen years and above were interviewed on one-and-one basis using questionnaires developed in reference to Adult AIDS Clinical Trial Group (AACTG) toolkit among them data from 404 were analyzed after cleaning. Data was entered and analyzed using Statistical Package for Social Sciences (SPSS) software where the P value of < 0.05 was accepted as being statistically significant. RESULTS: The overall adherence in the last month (missed less than three pills total) was 94.8% (383 out of 404). The main barrier to ART adherence was the fear of side effects (among 61.9% of the non adherent population) which included dizziness (18.1%) and headaches (15.4%). The standard wristwatch (39%) was found to be the most useful aid in enabling timely consumption of medication. Educational status (P = 0.018), drug using habits (P = 0.039) and the conducive environment at ART clinics (P = 0.004) were significantly associated with ART adherence. CONCLUSION: Improving better adherence may require a more holistic approach to treatment regimen and adapting it to patient daily routines. This study identifies issues such as pill count for assessing adherence, better access to health care facilities by clients, better access to medication, as well as improved nutritional support issues for better adherence by the population in the future.