Objective The study objective was to evaluate the effectiveness of an operational multidisciplinary antibiotic team, including an infectious disease physician and a clinical pharmacist, in reducing the hospital antimicrobial consumption and costs. Setting The 1800-bed University Hospitals of Nancy (France). Method A cluster controlled ‘before-after’ study was performed. The intervention group comprised 11 medical and surgical wards in settings where the operational antibiotic team was implemented, and the control group comprised 6 wards without this operational team. The ‘before’ period (2005) preceded the implementation of the operational team in the intervention group and ‘after’ (July 2007 to June 2008) followed its full implementation. Main outcome measure We compared consumption of antibiotics overall and by therapeutic class (in defined daily doses per 1,000 patient days) and cost savings (in €) between ‘before’ and ‘after’ in both groups (control and intervention), using a mixed effect linear model. Results The overall consumption of antibiotics decreased after implementation of the operational team by 33.6% in the intervention group and by 3.3% in the control group (P = 0.003). Compared with the control group, the decrease in antibiotic use in the intervention group was significantly higher for various therapeutic classes (broad-spectrum penicillins, injectable fluoroquinolones, glycopeptides) and specific drugs (imipenem, ciprofloxacin, teicoplanin). For the same activity, the total cost savings were 14-fold higher in the intervention group. Conclusion Establishment of an operational multidisciplinary team may be an effective way to reduce hospital antibiotic use and cost, with a good acceptance rate among prescribers.