Potentially harmful polypharmacy is a growing public health concern. This article aims to evaluate the effectiveness of a structured Team Approach to Polypharmacy Evaluation and Reduction (AusTAPER) framework. We recruited patients at metropolitan hospitals for a randomised controlled trial with 12 months of follow-up. The intervention included a comprehensive medicines history, multidisciplinary meeting and medicines review prior to discharge, with engagement with the participants' general practitioner extending after discharge. The primary outcome was the change in the number of regular medicines used at 12 months from baseline. A cost consequence was performed to estimate costs per participant during the study period. There were 98 participants enrolled in the study. The number of regular medicines was significantly reduced from baseline in both groups (-1.7 ± 4.3, t = 2.38, P = 0.02 in the control group vs -2.7 ± 3.6, t = 4.48, P = 0.0001 in the intervention group), although there was no statistical difference detected between the two groups (1.0 (SE 0.9), t = 1.03, P = 0.31). The intervention was estimated to cost AU$644.17 and was associated with cost savings of AU$552.53 per participant in sustained reduced medicines cost. Health outcomes and healthcare costs were similar in both groups. Medicines were significantly reduced in both groups, with a trend to a larger reduction in medicines at 12 months in the intervention group. The intervention cost was approximately offset by sustained reduced medicines cost, although these results should be regarded cautiously because of the absence of significance in the differences in outcomes between groups.