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INTRODUCTION: Tuberculosis (TB) is a communicable infectious disease caused by Mycobacterium Tuberculosis (MTB). Treatment for latent TB infection (LTBI) is an important strategy to reduce socioeconomic burden of HIV/TB coinfection by providing Isoniazid prophylaxis therapy (IPT) for people living with HIV (PLHIV). Appropriate initiation and good patient adherence are crucial to achieve this. OBJECTIVES: The main aim of this study was to assess level of IPT initiation appropriateness, ADR and patient adherence in HIV patients on IPT during follow up in university of Gondar referral hospital. METHODS: A facility based cross sectional study design was conducted and simple random sampling technique was used for selected populations. A structured questionnaire was used and IPT initiation appropriateness was determined against WHO guideline; patient adherence was evaluated according to Morisky adherence scale and self reported ADR was also assessed. Data was analyzed using SPSS version 21 for windows and statistically significance considered when p<0.05. RESULTS: According to Morisky adherence scale 121 (81.2%) HIV patients were having good adherence with 95% CI (77.8–84.6). IPT adherence having statistically significant association with pill burden (<5pills per day, COR 10.14 (4.03-25.52) and duration of therapy (>2 hour, AOR 31.7 (3.37-298)). Out of a total of 52 patients who took IPT and experienced ADR, 21 patients (40.38%) were on INH for less than 3 month and the majority (59.62%) took IPT longer. The most common ADR encountered was constipation (30.8%). The obtained appropriateness level was 116 (77.9%) and the remaining 33 (22.1 %) initiation of isoniazid prophylaxis therapy was found to be inappropriate. CONCLUSION: The level of adherence to IPT was generally high in PLHIV. Participants who need <2 hours to reach hospital had good adherence than those who need more than 2 hours. Patient who had baseline active TB symptom and contraindication at initiation suffer more from ADR and associated non adherence through therapy than those with appropriate initiation at baseline. Most ADRs were occurred in the last three month of therapy. Overall IPT initiation appropriateness was high.