Objective. To compare the effects of different skin preparation solutions on surgical-site infection rates. design. Three skin preparations were compared by means of a sequential implementation design. Each agent was adopted as the preferred modality for a 6-month period for all general surgery cases. Period 1 used a povidone-iodine scrub-paint combination (Betadine) with an isopropyl alcohol application between these steps, period 2 used 2% chlorhexidine and 70% isopropyl alcohol (ChloraPrep), and period 3 used iodine povacrylex in isopropyl alcohol (DuraPrep). Surgical-site infections were tracked for 30 days as part of ongoing data collection for the National Surgical Quality Improvement Project initiative. The primary outcome was the overall rate of surgical-site infection by 6-month period performed in an intent-to-treat manner. setting. Single large academic medical center. patients. All adult general surgery patients. results. The study comprised 3,209 operations. The lowest infection rate was seen in period 3, with iodine povacrylex in isopropyl alcohol as the preferred preparation method (3.9%, compared with 6.4% for period 1 and 7.1% for period 2; ). In subgrouPp.002 p analysis, no difference in outcomes was seen between patients prepared with povidone-iodine scrub-paint and those prepared with iodine povacrylex in isopropyl alcohol, but patients in both these groups had significantly lower surgical-site infection rates, compared with rates for patients prepared with 2% chlorhexidine and 70% isopropyl alcohol (4.8% vs 8.2%; Pp.001). conclusions. Skin preparation solution is an important factor in the prevention of surgical-site infections. Iodophor-based compounds may be superior to chlorhexidine for this purpose in general surgery patients.