Background Drug-related problems (DRP) following hospital discharge may cause morbidity, mortality and hospital re-admissions. It is unclear whether a clinical medication review (CMR) and counseling at discharge is a cost-effective method to reduce DRP. Objective To assess the effect of a CMR on health care utilization and to investigate whether CMR is a cost-effective method to reduce DRP in older polypharmacy patients discharged from hospital. Setting 24 community pharmacies in the Netherlands. Method A cluster-randomized controlled trial with an economic evaluation. Community pharmacies were randomized to those providing a CMR, counseling and follow-up at discharge and those providing usual care. Main outcome measures Change in the number of DRP after 1 year of follow-up and costs of health care utilization during follow-up. In 216 patients the use of health care was prospectively assessed. Missing data on effects and costs were imputed using multiple imputation techniques. Bootstrapping techniques were used to estimate the uncertainty around the differences in costs and incremental cost-effectiveness ratios. Results CMR resulted in a small reduction of DRP. The proportion of patients readmitted to the hospital during 6 months of follow-up was significantly higher in the intervention group than in the control group (46.4 vs. 20.9%; p < 0.05). Health care costs were higher in the intervention group, although not statistically significant. The costs of reducing one DRP by a CMR amounted to €8270. Conclusion A CMR in vulnerable older patients at hospital discharge led to a small reduction in DRP. Because of a significantly higher use of health care and higher number of re-hospitalisations post CMR, the present study data indicate that performing the intervention in this patient population is not cost-effective.