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The use of a topical skin protectant (TSP) as a means of protecting troops from percutaneous chemical warfare agent (CWA) exposure has been proposed since these weapons were first used during World War I. The TSP is applied to vulnerable skin surfaces prior to entry into a chemical combat area. In 1990, the US Army Medical Research Institute of Chemical Defense transferred two non-reactive TSPs into advanced development. Following US Food and Drug Administration approval, the final product is expected to be available to soldiers in 1999. A continuing research effort is designed to develop a second-generation TSP that will increase effectiveness and also decontaminate CWAs into non-toxic products. We identified a list of 29 reactive moieties as potential additives to the TSP formulation. All candidate formulations are evaluated in a decision tree network, consisting of a series of 11 efficacy testing models. A prototype formulation (ICD 2701) containing the reactive ingredient S-330 has dramatically improved the protection against saturated sulfur mustard vapor. In addition, we have discovered a compound (ICD 2837) that significantly increases the skin’s natural resistance to CWA penetration. Our goal is to transfer a significantly improved TSP formulation into advanced development by 1999. [ABSTRACT FROM AUTHOR]