Background Medication-related problems are common after hospitalization, for example when changes in patients’ medication regimens are accompanied by insufficient patient education, poor information transfer between healthcare providers, and inadequate follow-up post-discharge. We investigated the effect of a pharmacy-led transitional care program on the occurrence of medication-related problems four weeks post-discharge. Methods A prospective multi-center before-after study was conducted in six departments in total of two hospitals and 50 community pharmacies in the Netherlands. We tested a pharmacy-led program incorporating (i) usual care (medication reconciliation at hospital admission and discharge) combined with, (ii) teach-back at hospital discharge, (iii) improved transfer of medication information to primary healthcare providers and (iv) post-discharge home visit by the patient’s own community pharmacist, compared with usual care alone. The difference in medication-related problems four weeks post-discharge, measured by means of a validated telephone-interview protocol, was the primary outcome. Multiple logistic regression analysis was used, adjusting for potential confounders after multiple imputation to deal with missing data. Results We included 234 (January-April 2016) and 222 (July-November 2016) patients in the usual care and intervention group, respectively. Complete data on the primary outcome was available for 400 patients. The proportion of patients with any medication-related problem was 65.9% (211/400) in the usual care group compared to 52.4% (189/400) in the intervention group (p = 0.01). After multiple imputation, the proportion of patients with any medication-related problem remained lower in the intervention group (unadjusted odds ratio 0.57; 95% CI 0.38–0.86, adjusted odds ratio 0.50; 95% CI 0.31–0.79). Conclusions A pharmacy-led transitional care program reduced medication-related problems after discharge. Implementation research is needed to determine how best to embed these interventions in existing processes.