Current assessment of drug-drug interaction (DDI) prediction success is based on whether predictions fall within a two-fold range of the observed data. This strategy results in a potential bias toward successful prediction at lower interaction levels [ratio of the area under the concentration-time profile (AUC) in the presence of inhibitor/inducer compared with control is <2]. This scenario can bias any assessment of different DDI prediction algorithms if databases contain large proportion of interactions in this lower range. Therefore, the current study proposes an alternative method to assessprediction success with a variable prediction margin dependent on the particular AUC ratio. The method is applicable for assessment of both induction and inhibition-related algorithms. The inclusion of variability into this predictive measure is also considered using midazolam as a case study. Comparison of the traditional two-fold and the new predictive method was performed on a subset of midazolam DDIs collated from previous databases; in each case, DDIs were predicted using the dynamic model in Simcyp® simulator. A 21% reduction in prediction accuracy was evident using the new predictive measure, in particular at the level of no/weak interaction (AUC ratio <2). However, inclusion of variability increased the prediction success at these levels by two-fold. The trend of lower prediction accuracy at higher potency of DDIs reported in previous studies is no longer apparent when predictions are assessed via the new predictive measure. Thus, the study proposes a more logical method for the assessment of prediction success and its application for induction and inhibition DDIs.