Pharmacists’ role may be ideal for improving rationality of drug prescribing practice. We aimed to study the impact of multifaceted pharmacist interventions on antibiotic prophylaxis in patients undergoing clean or clean-contaminated operations in cardiothoracic department.A pre-test–post-test quasiexperimental study was conducted in a cardiothoracic ward at a tertiary teaching hospital in Suzhou, China. Patients admitted to the ward were collected as baseline group (2011.7–2012.12) and intervention group (2013.7–2014.12), respectively. The criteria of prophylaxis antibiotic utilization were established on the basis of the published guidelines and official documents. During the intervention phase, a dedicated pharmacist was assigned and multifaceted interventions were implemented in the ward. Then we compared the differences in antibiotic utilization, bacterial resistance, clinical and economic outcomes between the 2 groups. Furthermore, patients were collected after the intervention (2015.1–2015.6) to evaluate the sustained effects of pharmacist interventions.412 and 551 patients were included in the baseline and intervention groups, while 156 patients in postintervention group, respectively. Compared with baseline group, a significant increase was found in the proportion of antibiotic prophylaxis, the proportion of rational antibiotic selection, the proportion of suitable prophylactic antibiotic duration, and the proportion of suitable timing of administration of the first preoperative dose (P < 0.001). Meanwhile, a significant reduction was seen in the rate of unnecessary replacement of antibiotics and the rate of unnecessary combinations (P < 0.001). Besides, pharmacist intervention resulted in favorable outcomes with significantly decreased rates of surgical site infections, prophylactic antibiotic cost, and significantly shortened length of stay (P < 0.05). Furthermore, there were also significant decreases of the rates of antibiotic resistant enterobacter cloacae, klebsiella pneumonia, and staphylococcus aureus (P < 0.05). Moreover, the effects were sustained after discontinuation of the active interventions, as shown in prophylactic antibiotic utilization data.Pharmacist interventions in cardiothoracic surgery result in a high adherence to evidence-based treatment guidelines and a profound culture change in drug prescribing with favorable outcomes. The effects of pharmacist intervention are sustained and the role of pharmacists is emphasized for rational medication and optimal outcomes in clinical treatment.