Objective To evaluate studies assessing the effectiveness of a bundle of nasal decolonization and glycopeptide prophylaxis for preventing surgical site infections caused by Gram positive bacteria among patients undergoing cardiac operations or total joint replacement procedures. Design Systematic review and meta-analysis. Data sources PubMed (1995 to 2011), the Cochrane database of systematic reviews, CINAHL, Embase, and clinicaltrials.gov were searched to identify relevant studies. Pertinent journals and conference abstracts were hand searched. Study authors were contacted if more data were needed. Eligibility criteria Randomized controlled trials, quasi-experimental studies, and cohort studies that assessed nasal decolonization or glycopeptide prophylaxis, or both, for preventing Gram positive surgical site infections compared with standard care. Participants Patients undergoing cardiac operations or total joint replacement procedures. Data extraction and study appraisal Two authors independently extracted data from each paper and a random effects model was used to obtain summary estimates. Risk of bias was assessed using the Downs and Black or the Cochrane scales. Heterogeneity was assessed using the Cochran Q and I2 statistics. Results 39 studies were included. Pooled effects of 17 studies showed that nasal decolonization had a significantly protective effect against surgical site infections associated with Staphylococcus aureus (pooled relative risk 0.39, 95% confidence interval 0.31 to 0.50) when all patients underwent decolonization (0.40, 0.29 to 0.55) and when only S aureus carriers underwent decolonization (0.36, 0.22 to 0.57). Pooled effects of 15 prophylaxis studies showed that glycopeptide prophylaxis was significantly protective against surgical site infections related to methicillin (meticillin) resistant S aureus (MRSA) compared with prophylaxis using β lactam antibiotics (0.40, 0.20 to 0.80), and a non-significant risk factor for methicillin susceptible S aureus infections (1.47, 0.91 to 2.38). Seven studies assessed a bundle including decolonization and glycopeptide prophylaxis for only patients colonized with MRSA and found a significantly protective effect against surgical site infections with Gram positive bacteria (0.41, 0.30 to 0.56). Conclusions Surgical programs that implement a bundled intervention including both nasal decolonization and glycopeptide prophylaxis for MRSA carriers may decrease rates of surgical site infections caused by S aureus or other Gram positive bacteria.