A meta-analysis was performed to investigate whether a switch from beta-lactams to glycopeptides for cardiac surgery prophylaxis should be advised. Results of 7 randomized trials (5761 procedures) that compared surgical site infections (SSIs) in subjects receiving glycopeptide prophylaxis with SSIs in those who received beta -lactam prophylaxis were pooled. Neither agent proved to be superior for prevention of the primary outcome, occurrence of SSI at 30 days (risk ratio [RR], 1.14; 95% confidence interval [CI], 0.91-1.42). In subanalyses, beta-lactams were superior to glycopeptides for prevention of chest SSIs (RR, 1.47; 95% CI, 1.11-1.95) and approached superiority for prevention of deep-chest SSIs (RR, 1.33; 95% CI, 0.91-1.94) and SSIs caused by gram-positive bacteria (RR, 1.36; 95% CI, 0.98-1.91). Glycopeptides approached superiority to beta-lactams for prevention of leg SSIs (RR, 0.77; 95% CI, 0.58-1.01) and were superior for prevention of SSIs caused by methicillin-resistant gram-positive bacteria (RR, 0.54; 95% CI, 0.33-0.90). Standard prophylaxis for cardiac surgery should continue to be beta-lactams in most circumstances.