For health care institutions, intraoperative prep agents are a critical link in combating surgical site infections and the associated economic burden. The question remains, is there an intraoperative prep agent that is truly superior to the others? We conducted a literature review to examine available empirical evidence related to intraoperative prep agents used in our health system for open abdominal, general surgery procedures: povidone-iodine, chlorhexidine gluconate, parachoroxylenol, and iodine povacrylex in 74% isopropyl alcohol. Intraoperative surgical skin prep studies were limited in providing empirical evidence to support one superior prep agent. Each prep agent has a specific mechanism of action along with specific advantages and disadvantages. We concluded that no one perioperative skin prep agent is superior in all clinical situations. Factors to consider when choosing an appropriate intraoperative skin prep agent include contraindications, environmental risks, the patient's allergies and skin condition, the surgical site, the manufacturer recommendations for the prep agent, and surgeon preference.