Infections associated with percutaneously implanted devices, such as pacemakers, internal cardiac defibrillators, and endovascular prostheses, create difficult and complex clinical scenarios because management can entail complete device removal, antibiotic therapy, and prolonged hospitalization. A source for pathogens is often thought to be the skin surface, making skin preparation at the time of the procedure a critical part of minimizing implantation of infected devices and prostheses. The most common skin preparation agents used today include products containing iodophors or chlorhexidine gluconate. Agents are further classified by whether they are aqueous-based or alcohol-based solutions. Traditional aqueous-based iodophors, such as povidone-iodine, are one of the few products that can be safely used on mucous membrane surfaces. Alcohol-based solutions are quick, sustained, and durable, with broader spectrum antimicrobial activity. These agents seem ideal for percutaneous procedures associated with prosthesis implantation, when it is critical to minimize skin colony counts to prevent hardware infection.