Efficient and accurate prediction for drugs’ potential to cause rare and severe adverse drug reactions (ADRs) is needed to facilitate the evaluation of risk-benefit ratio of drug candidates during drug development. Severe skin disorders like the Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which are life-threatening dermatological conditions, are such ADRs that have not received sufficient attention so far. In this study, a total of 1127 marketed drugs were screened for their potential to cause SJS/TEN, of which 255 were found to cause SJS/TEN and 239 were unlikely to cause SJS/TEN. One-class classification method was used to develop multiple prediction models. An applicability domain was determined to define the applicability of the model. Ensemble method was used to develop ensemble models to improve prediction ability. The final ensemble model achieved a sensitivity and specificity of 81 % and 67.4 %, respectively, when estimated using the external 5-fold cross validation method, and a sensitivity of 66.7 % when assessed using an external positive set. The results suggest the methods used in this study are potentially useful for facilitating the prediction of rare and severe ADRs.