Background The merits of a systems approach to preoperative surgical patient skin preparation are presented. A “system” may be defined as the addition of an antiseptic bath(s) or shower(s) within 24 hours before the application of a Food and Drug Administration–compliant patient preoperative skin preparation at the time of surgery. The expected outcome from this added effort is a further reduction in the transient and normal flora that contaminate the skin surrounding the operative site, and contribute to surgical infections. The Centers for Disease Control and Prevention has recommended the addition of this step to the preoperative site preparation regimen. Methods A human in vivo study comparing an alcohol-based (ethanol) system to an iodine-based approach, and 2 sets of clinical observations, are presented here. Results The data confirm the utility of the systems approach. The in vivo study demonstrates that significant reductions (≥2 log 10) in normal and transient flora can be achieved quickly and maintained out to 72 hours after the surgery, allowing for wound closure in a prolonged state of skin antisepsis. Clinical observations support the in vivo findings. After initiation of the system, the infection rates for the monitored procedures have decreased. Conclusions The data presented here delineate the merits of a systems approach to preoperative surgical patient skin preparation. This approach has a positive impact on infection rates and may reduce the additional costs associated with this preventable event.