We analyzed retrospectively, by use of logistic regression, the role of the phenotypic susceptibility score (PSS) as a determinant of virologic outcome in a study of treatment-experienced human immunodeficiency virus (HIV) type 1-infected subjects. A model for PSS in which each drug was treated equally and scored as active or inactive was not predictive of HIV-1 RNA load (VL) suppression. However, weighting the potential contribution of each drug on the basis of inferred potency and by use of a continuous scale to quantify drug susceptibility revealed significant associations between PSS and outcome. Entry VL was a strong independent predictor of therapy outcome, and PSS was a strong predictor of the magnitude of the initial decrease in VL. This suggests that the prospective evaluation of PSS to identify regimens that maximize decreases in VL to reduce the probability of virologic rebound could improve antiretroviral treatment.