The episode traces the development and impact of the Aqueous Prep Trial, a large comparative-effectiveness study evaluating iodine versus chlorhexidine gluconate for skin preparation in open fractures. Built on insights from the FLOW trial, the study enrolled over 1,600 patients across 15 international centers and emphasized a patient-engaged design. Despite expectations from prior alcohol-based literature, results showed no difference between aqueous solutions, suggesting either option is appropriate when alcohol is avoided for open wounds. The conversation highlights how pragmatic practice patterns—such as widespread pre-wash alcohol use on intact skin—shaped outcomes and underscored the value of incremental advances in managing complex injuries. Beyond its findings, the trial marks a milestone for emerging surgeon-scientists and sets the stage for forthcoming alcohol-based comparisons within the broader PREP-IT program.