One of the many challenges related to the implementation of antiretroviral therapy (ART) is the occurrence of toxicity. Drug toxicity may lead to drug substitution, morbidity and mortality risk factors of HIV/AIDS patients. The objective of this study was to investigate the risk factors associated with toxicity occurrences among HIV/AIDS patients based on data obtained from Dilla and Hawassa Referral Hospitals recorded from June 2007 - June 2009. Logistic and multiple regression methods were applied. The results of the analysis was discussed: the occurrence of toxicity, the causes of change in drug regimen, the main risk factors associated with drug change and the risk of being toxic, predictors affecting the base function status, factors that affected CD4 count, CD8 count, Base line functional status and Base line WHO clinical stage of patients. The analysis would help physicians shed some light on toxicity and its causes, and would be useful in determining the effect of drug regimen...