Background: Antiretroviral therapy (ART) adverse events can range from acute and potentially life threatening to chronic and insidious. Serious life-threatening events require the immediate discontinuation of all ARV drugs and re-initiation of an alternative regimen. Objective: To assess the time to developments of major adverse drug reaction and its determinants among adult HIV patients on ART in Felege Hiwot referral hospital, North West Ethiopia, 2017. Methods: Retrospective cohort study was conducted among patients on ART from July1/2011 - June 30/2016 at Felege Hiwot referral hospital. Data were collected using checklist and entered EPI info version 7, and analyzed using SPSS version 21 Descriptive statistics and survival analysis were computed. The p-value, hazard ratio and its confidence interval was used to show presence and strength of association between different predictor variables and time of ADRs. Results: A total of 602 subjects were followed for different period and gave 1435 person years of observation. The study showed that the overall rate of occurrence of major ADR was 4.3/100PY. The probability of surviving without major ADRS at the end of first half, one, two and end of follow up years were 0.94, 0.91, 0.89 and 0.88 respectively. Individuals with no formal education and primary education were more likely to report ADRs [AHR =8, 95 % CI: 2.53- 25.20, AHR = 4.9, 95 % CI: 1.65- 14.44]. Individuals working in NGOs were at risk of ADRs [AHR =4.3, 95 % CI: 1.42 – 13.31]. The study also showed that individuals with WHO stage II, III, IV were at risk of ADRs [AHR=4, 95 % CI: 1.33 -11.93, AHR=5.3, 95 % CI: 2.02-13.79 and AHR=7, 95 % CI: 2.51-20.10]. Eventually, patient who didn’t take (OI) prophylaxis [AHR=3.2, 95 % CI: 1.47-7.08] were significantly associated with time to develop ADRs among HIV positive patients. Conclusions and Recommendations: In this study, the rate of major adverse drug reaction was found to be high and most of the change occurred within a year after initiation of HAART. Educational status, occupation, advanced clinical stage and OI prophylaxis therapy were predictors of time to the development of major ADRs. The health workers need to give special attention and continuous counseling for non-educated patient, patient with clinical stage II and above and patients who didn’t take OI prophylaxis to prevent associated ADRs.