The PREPARE Trial was a cluster-randomized, crossover trial part of the PREP-IT program, which compared alcohol-based anti-septic solutions of iodine povacrylex vs. chlorhexidine gluconate in operative fracture patients. THE PREPARE Trial included a total of 8485 patients who underwent fracture fixation: 1700 patients with open limb fractures and 6785 with closed lower-limb or pelvic fractures. Randomization occurred at the hospital level. The primary outcome of interest was the incidence of surgical-site infection, which included superficial incisional infections within 30 days and deep incisional or organ-space infections within 60 days post-surgery. Secondary outcomes included unplanned fracture-related reoperations and serious adverse events. The iodone povacrylex group (77/3205; 2.4%) had a lower incidence of surgical site infections compared to chlorhexidine (108/3272; 3.3%) in closed-fracture patients [OR, 0.74; 95% CI, 0.55 to 1.00; p=0.049]. The rates were similar in open-fracture patients between the iodine (54/3272; 6.5%) and chlorhexidine (60/3272; 7.3%) [OR, 0.86; 95% CI, 0.58 to 1.27; p=0.45]. In the closed-fracture group, 5.5% in the iodine group and 5.9% in the chlorhexidine group underwent unplanned reoperations [OR, 0.96; 95% CI, 0.77 to 1.20]. In the open-fracture group, the figures were 16.1% for iodine and 14.5% for chlorhexidine [OR, 1.16; 95% CI, 0.87 to 1.54]. The results of this trial suggest that an iodine-alcohol solution for pre-operative skin antisepsis could reduce the risk of surgical site infection in closed fracture patients, but may not provide any benefit over chlorhexidine-alcohol solutions for open fracture patients.