Dimethyl sulfoxide (DMSO), when used as a percutaneous carrier or as a required solvent for drugs may have modulating effects on expected drug mechanisms and untoward effects on subject tissues. In this particular study, anhydrous DMSO was used as a vehicle for peptide caspase inhibitors of mustard gas (HD)-induced apoptosis in hairless guinea pig skin. Results of caspase inhibition on HD-induced apoptosis realized from this study are the subject of a subsequent companion publication. The thrust of the present manuscript is the observed effects of DMSO on hairless guinea pig skin when used as a drug vehicle. DMSO (18μl) was applied topically to skin sites as a vehicle control 30 minutes prior to neat HD-vapor exposure (7∼8 min). Unexposed hairless guinea pig skin sites also treated for 30 minutes with DMSO were used as controls. Selected exposed and unexposed skin sites, harvested at 6h and 24h postexposure, were fixed in combined aldehydes, dehydrated in graded ethanols and either paraffin-processed for routine histopathology or epoxy embedded for ultrastructural pathology. In the case of HD-exposed skin sites pretreated with DMSO, morphological results indicated a marked acceleration and exacerbation of the characteristic pathologies typically described for routine HD skin exposures. At 6h postexposure, epidermal basal cells presented pyknotic nuclear and degenerative cytopathologies usually not seen until later time periods. Also at this time period, presentations of microvesicles at the basement membrane zone usually not in evidence until 10∼12h postexposure, were a persistent feature of the pathology. At 24h postexposure, cleavage and separation of epidermis and dermis were more expansive than with typical HD exposure. In addition, unexposed control sites treated with DMSO presented an exaggerated inflammatory response of the papillary dermis usually not seen in control skin. The “inflammation-primed” dermis induced by DMSO was composed of typical vascular and extravasated inflammatory cellular elements and may be responsible for the acceleration and exacerbation of the characteristic HD-induced skin pathology observed in this study.