OBJECTIVES The objective of this study was to estimate the incremental cost-effectiveness ratio (ICER) of a medication review with follow-up (MRF) service for older people with polypharmacy in community pharmacies against the alternative of receiving usual dispensing. METHODS The study was designed as a longitudinal cluster randomized trial carried out over six months of follow-up. The target population consisted of older people (≥65 years) with polypharmacy (≥5 drugs) and the study was conducted in 178 community pharmacies in Spain. A total of 1,403 patients were enrolled, 688 in the intervention group (IG) and 715 in the control group (CG). The analysis adopted the perspective of the National Health Service (NHS). In order to analyze the uncertainty of ICER results, we performed a nonparametric bootstrapping with 5,000 replications.  RESULTS Both groups reduced the average number of prescribed medications, although this reduction was greater in the IG (0.28 drugs; p<0.001) than in the CG (0.07 drugs; p=0.063). Patients in the IG showed an improvement in their quality of life by 0.0528 in the utility score (p<0.001). By contrast, patients in the CG showed no differences in their quality of life by 0.0022 in the utility score (p=0.815). We obtained an ICER of €8,542/QALY and €6,777/QALY for the first and second scenario respectively, and a MRF as dominant strategy for the third, fourth and fifth scenario. For a willingness to pay of €30,000/QALY, the probability of the MRF being cost-effective, compared to usual dispensing, is in a range between 98.2% and 100% for the five scenarios. CONCLUSIONS MRF is an effective intervention for optimizing prescribed medication and improving the quality of life of older people with polypharmacy in community pharmacies. The results from the cost-utility analysis suggest that MRF is cost-effective.