BACKGROUND: Treatment with effective antiretroviral therapy (ART) reduces viral load as well as HIV-related morbidity and mortality in HIV-positive patients. Despite the expanded availability of antiretroviral therapy around the world, virological failure remains a serious problem for HIV-positive patients. Thus, Machine learning predictive algorithms have the potential to improve the quality of care and predict the needs of HIV patients by analyzing huge amounts of data, and enhancing prediction capabilities. This study used different machine learning classification algorithms to predict the features that cause virological failure in HIV-positive patients. METHOD: An institution-based secondary data was used to conduct patients who were on antiretroviral therapy at the University of Gondar Comprehensive and Specialized Hospital from January 2020 to May 2022. Patients' data were extracted from the electronic database using a structured checklist and imported into Python version three software for data pre-processing and analysis. Then, seven supervised classification machine-learning algorithms for model development were trained. The performances of the predictive models were evaluated using accuracy, sensitivity, specificity, precision, f1-score, and AUC. Association rule mining was used to generate the best rule for the association between independent features and the target feature. RESULT: Out of 5264 study participants, 1893 (35.06%) males and 3371 (64.04%) females were included. The random forest classifier (sensitivity = 1.00, precision = 0.987, f1-score = 0.993, AUC = 0.9989) outperformed in predicting virological failure among all selected classifiers. Random forest feature importance and association rules identified the top eight predictors (Male, younger age, longer duration on ART, not taking CPT, not taking TPT, secondary educational status, TDF-3TC-EFV, and low CD4 counts) of virological failure based on the importance ranking, and the CD-4 count was recognized as the most important predictor feature. CONCLUSION: The random forest classifier outperformed in predicting and identifying the relevant predictors of virological failure. The results of this study could be very helpful to health professionals in determining the optimal virological outcome.