Alcohol-based products for skin antisepsis have a long history of safety and efficacy in the United States and abroad. However, alcohol alone lacks the required antimicrobial persistence to provide for the sustained periods of skin antisepsis desired in the clinical environment. Therefore, alcohol-based products must have a preservative agent such as iodine/iodophor compounds, chlorhexidine gluconate, or zinc pyrithione, to extend its antimicrobial effects. Iodine, iodophors, and chlorhexidine gluconate are well-characterized antimicrobials and preservatives. The thrust of our effort was to examine the characteristics of the lesser-known zinc pyrithione and to evaluate its utility as a preservative in the formulation of alcohol-based products for skin antisepsis. This work includes a literature review of current zinc pyrithione applications in drugs and cosmetics, a safety and toxicity evaluation, consideration of the proposed mechanisms of antimicrobial action, in vitro and in vivo efficacy data, and a discussion of the mechanisms that confer the desired antimicrobial persistence. In addition, alcohol-based, zinc pyrithione-preserved, commercially available products of skin antisepsis are compared with other commercially available antimicrobials used for skin antisepsis and with additional alcohol-based products with different preservatives. The authors' conclusion is that zinc pyrithione is not only a safe and effective antimicrobial but that its use in certain alcohol-based formulations results in antimicrobial efficacy exceeding that of iodine and chlorhexidine gluconate.