This episode examines a landmark NEJM trial comparing iodine–alcohol and chlorhexidine–alcohol for antisepsis in extremity fracture surgery. The investigators describe a large, pragmatic, cluster-crossover RCT enrolling over 8,500 patients, powered to assess open and closed fractures separately. Iodine–alcohol lowered surgical site infection rates in closed fractures with a meaningful relative reduction, prompting discussion on implementation, behavioral nudges, and stepped-wedge designs to accelerate practice change. The conversation highlights evolving trial methods, stakeholder engagement, and the challenge of translating strong evidence into widespread adoption.