A B S T R A C TBackground: Surgical site infection (SSI) is a dreaded postoperative complication. Although preoperative skin cleansing in order to prevent surgical site infection (SSI) is standard surgical practice, there is clinical equipoise concerning whether povidone iodine (PI) or chlorhexidine alcohol (CHA) is the antiseptic agent of choice. Objectives: To determine whether CHA or PI is the preferred preoperative skin preparation for reducing SSI in clean, clean-contaminated and contaminated surgery. Search methods: PubMed, Embase, and gray literature sources were searched for randomized controlled trials (RCTs) comparing both CHA and PI between 1980 and 2014. Comparative RCTs of preoperative CHA versus PI studying SSI in clean, clean-contaminated and contaminated surgery were included. Risk of bias was assessed using Cochrane risk of bias. Main result: We identified six eligible studies with an overall 2484 participants. The overall rate of SSI was 6.8% in the CHA group versus 11.0% in the PI group (P < 0.0002). CHA was superior to PI in the prevention of SSI with a pooled RR of 0.62 (95% CI, 0.48-0.81). Conclusions: Preoperative surgical skin preparation with CHA is more effective than PI in preventing SSI across clean and clean-contaminated surgery. Further studies should evaluate the effectiveness of CHA versus PI in contaminated surgery.