Background: Lost to follow up (LTFU) from antiretroviral therapy (ART) is a global challenge with prevalence of 24.5% which exceeds the target of World health organization. In Ethiopia, its prevalence ranges from 18.0 to 31.4%. Now the magnitude of LTFU is increased as compared to previous years in East Gojjame zone. It causes drug resistance, immunological failure, illness and death. Objective: To identify determinants of LTFU from ART among adult patients who have been ever attending at high load antiretroviral therapy health centers in East Gojjam Zone, North-West Ethiopia. Methods: Unmatched case control study was conducted with sample size of 1275 (425 cases and 850 controls) from March 25 to May 15/2019 at high load ART health centers in East Gojjam Zone. All cases were included whereas controls were selected by simple random sampling. Structured questionnaire and data extraction tool were used for data collection. Data were coded and entered using Epi-data version 3.1, then exported to Statistical Package for Social Science version 23 for analysis. After Bi-variable binary logistic regression analysis, all variables with a p-value < 0.2 were entered into Multivariable logistic regression and p-value < 0.05 was considered as significantly associated with the outcome variable. Results: Starting with Stavudine+Lamivudine+Efaverinez (d4t+3TC+EFV) [AOR=5.21, 95%CI; 1.73−15.69] as compared to starting with Tenofovir+Lamivudine+Efavinez, being married and lived separately [Adjusted Odds Ratio (AOR) =3.10, 95%CI; 2.06-4.65] as compared to married and lived together, daily laborer [AOR=2.81, 95%CI; 1.52-5.20] as compared to governmental employee, <12months on ART [AOR= 2.91, 95%CI; 2.41-6.36] as compared to ≥ 24 months on ART were major factors that increased the odds of LTFU. Being college and above [AOR=0.41, 95%CI; 0.16-0.68 were protective for LTFU as compared to have no formal education. Conclusion: Married and lived separately, daily laborer, college and above education, <12 months on ART, baseline drug regimen and having tuberculosis were major determinants of LTFU from ART. Therefore, patients’ education and counseling should be strengthened. Keywords: Adult patients, Antiretroviral therapy, Associated factors, Loss to follow up, East Gojjam Zone