The National Drug File Reference Terminology contains a novel reference hierarchy to describe physiologic effects (PE) of drugs. The PE reference hierarchy contains 1697 concepts arranged into two broad categories; organ specific and generalized systemic effects. This investigation evaluated the appropriateness of the PE concepts for classifying a random selection of commonly prescribed medications. Ten physician reviewers classified the physiologic effects of ten drugs and rated the accuracy of the selected term. Inter reviewer agreement, overall confidence, and concept frequencies were assessed and were correlated with the complexity of the drug's known physiologic effects. In general, agreement between reviewers was fair to moderate (kappa 0.08-0.49). The physiologic effects modeled became more disperse with drugs having and inducing multiple physiologic processes. Complete modeling of all physiologic effects was limited by reviewers focusing on different physiologic processes. The reviewers were generally comfortable with the accuracy of the concepts selected. Overall, the PE reference hierarchy was useful for physician reviewers classifying the physiologic effects of drugs. Ongoing evolution of the PE reference hierarchy as it evolves should take into account the experiences of our reviewers.