Aims The aim was to assess the impact of a campaign for general practitioners (GPs) to reduce clinically‐important drug–drug interactions (DDIs) in poly‐treated elderly patients. Methods We compiled a list of 53 DDIs and analyzed reimbursed prescriptions dispensed to poly‐treated (≥four drugs) elderly (>65 years) patients in the Emilia Romagna region during January 2011–June 2011 (first pre‐intervention period), January 2012–June 2012 (second pre‐intervention period) and January 2013–June 2013 (post‐intervention period). Educational initiatives to GPs were completed in July 2012–December 2012. Pre‐test/post‐test analysis (2013 vs. 2012) was performed, also using predicted 2013 data (P < 0.01 for statistical significance). Results Despite the slight increase in poly‐therapy rate (16% in 2013, +1.5% from 2011), we found a stable or slightly declining number of potential DDIs for each elderly poly‐treated patient (~1.5). In 2013, 11 DDIs exceeded 5% of prevalence rate: antidiabetics‐β‐adrenoceptor blockers ranked first (20.3%), followed by ACE Inhibitors (ACEIs)/sartans‐non steroidal anti‐inflammatory drugs (NSAIDs) (16.4%), diuretics‐NSAIDs (13.6%), selective serotonin re‐uptake inhibitors (SSRIs)‐NSAIDs/acetyl salicylic acid (ASA) (12.7%) and corticosteroids‐NSAIDs/ASA (9.7%). A remarkable reduction emerged for NSAID‐related DDIs (diuretics‐NSAIDs peaked −14.5%; P < 0.01), whereas prevalence of antidiabetics‐β‐adrenoceptor blockers increased (+7.9%; P < 0.01). When using predicted values, the statistical significance disappeared for antidiabetics‐β‐adrenoceptor blockers (+1.3%; P = 0.04), whereas it persisted for almost all NSAIDs‐related DDIs: ACEIs/sartans‐NSAIDs (−3.0%), diuretics‐NSAIDs (−6.0%), SSRIs‐NSAIDs/ASA (−5.9%). Conclusions This campaign contained the burden of DDIs in poly‐treated elderly patients by 1) reducing most prevalent DDIs, especially NSAIDs‐related DDIs and 2) balancing the observed rise in poly‐therapy rate with stable rate in overall prescriptions of potentially interacting drugs per patient.