We report a significant reduction in the number of surgical site infections (SSIs) due to meticillin-resistant Staphylococcus aureus (MRSA) in patients undergoing cardiac surgery after the introduction of preoperative screening using a same-day polymerase chain reaction (PCR) test. This was an observational cohort study set in a cardiac surgery unit based in southwest England. We studied 1462 patients admitted for cardiac surgery between October 2004 and September 2006. The IDI MRSA PCR test was used preoperatively to screen 765 patients between October 2005 and September 2006. Patients identified as carriers were treated with nasal mupirocin ointment and topical triclosan for five days, with single-dose teicoplanin instead of flucloxacillin as perioperative antibiotic prophylaxis. The rate of SSI following cardiac surgery in this group was compared to 697 patients who underwent surgery without screening between October 2004 and September 2005. After introduction of PCR screening, the overall rate of SSI fell from 3.30% to 2.22% with a significant reduction in the rate of MRSA infections (relative risk reduction: 0.77; 95% confidence interval: 0.056-0.95). PCR screening combined with suppression of MRSA at the time of cardiac surgery is feasible in routine clinical practice and is associated with a significant reduction in subsequent MRSA SSIs.