Background: Adherence to antiretroviral therapy (ART) is crucial to ensure viral suppression, decrease the risk of disease progression and drug resistance. Non-adherence to ART, likewise, is common in all groups of treated individuals & lack of strict adherence to ART is considered to be one of the key challenges to AIDS care worldwide. Objective: To assess adherence to ART on currently changed guideline and factors associated with it among People Living with HIV/AIDS (PLWHA) attending ART unit at Bishofitu Hospital. Method: A cross sectional survey of 317 clients attending for ART at Bishofitu Hospital was carried out using both quantitative & qualitative design method. Using a structured and pre-tested questionnaire, data on drug adherence and other variables was collected through in-depth interview, peer educators FGD, patient’s self report (interview), pill count and by reviewing their clinical records. The nurse & ART Clinician who are working in the ART unit were involved in data collection after being trained. Ethical clearance was obtained from concerned bodies and consent was sought from the study subjects. Adherence is defined as the number of doses taken divided by the number of doses prescribed over a given period. It is considered as good if the patient took ≥ 95% of the prescribed doses correctly. Odds ratio was done to determine the strength of association for different variables. Major Findings The overall prevalence of HAART adherence was found to be, 398(95.4%) in this study. The highest proportion, 61 % of patients missed or delayed their doses due to simply forgetting & 47.4% due to being away from home & 29.4% being too busy. Independent positive predictors of HAART non adherence reported in this study comprise:-the participants who had: PLWHA’s residency far from Bishofitu hospital (>47 KM.), depression feelings , ART eligibility knowledge, medication adverse effect, history active substance uses, no adequate social support & one or two children under their care in the final adjusted multivariate analysis. Conclusions & Recommendations: The prevalence of ART adherence among clients using currently changed single combined fixed dose in this study was found higher than most studies done in developed countries & even much higher than the findings of other studies in Ethiopia. From these, we can infer that single & simplified ART has reduced the pill burden & helped the clients to take it at ease & this has increased the level of adherence behavior of clients, therefore continuous effort should be made to increase clients’ awareness to maintain the best level of adherence outcomes.