Sulfur mustard (HD; 2,2'-dichlorodiethyl sulfide) can produce incapacitating blisters in humans following dermal exposure. Most non-human animal models, however, do not form the large fluid-filled blisters observed in humans. Many models, nevertheless, do produce similar damage at the dermal/epidermal junction when evaluated by histopathology. In this study, it was observed that the hairless guinea pig (HGP) exhibits similar histopathological responses following exposure to HD vapor. Two sets of HGPs were exposed percutaneously for various lengths of time to HD vapor. In one set, the HGPs were sacrificed 24 h after exposure, and skin specimens were collected and processed for histopathology. In the other set, light reflectance was measured at skin test sites 4, 5, 6 and 24 h after exposure, to assess erythema. The Nikolsky's sign test was also performed 24 h after exposure by rotating a metal disk glued to the skin test site and inspecting the skin for loss of epidermis. Probit analysis of data indicated that the exposure durations that produced a 50% incidence of microblisters and Nikolsky's sign were ca. 7.5 and 4.5 min, respectively. Maximum erythema was observed 6 h following a 6 min exposure. Operating parameters for assessing the efficacies of skin protectants have been characterized.