Thirty studies containing 29,006 patients were included in this meta-analysis comparing chlorhexidine and povidone-iodine skin disinfectant solutions for the prevention of surgical site infection. The primary outcome of interest was the pooled incidence of post-operative surgical site infection. The secondary outcome of interest was the pooled incidence of skin-related adverse events. Sub-group analyses of the primary outcome by study design (randomized controlled trials (RCT), non-RCTs) and surgical environment (clean surgery, clean contaminated surgery) were performed. Results revealed the pooled surgical site infection rate to be significantly in favour of the chlorhexidine group compared to the povidone-iodine group. The pooled rate of skin-related adverse events was not significantly different between groups. In the sub-group analyses, the pooled surgical site infection rate was significantly in favour of the chlorhexidine group in the RCT-only analysis, clean surgery analysis, and clean-contaminated surgery analysis.