Abstract Vesicant-induced pathogenesis is initiated by rapid alkylation and cross-linking of DNA purine bases causing strand breaks leading subsequently to NAD depletion and cell death. We postulated that vesicants may also be associated with free radical-mediated oxidative stress distal to the site of exposure. To test this postulate in the lung, we injected 3 groups ( n = 8) of 5-month-old, male, athymic, nude mice, weighing 30–35 g with a single subcutaneous (s.c.) injection (5 μl/mouse) of butyl 2-chloroethyl sulfide (BCS), a monofunctional sulfur mustard analog. After 1, 24 and 48 h, we euthanized the treated mice along with 2 untreated control mice at each time point. We then pooled the control mice in one group ( n = 6) and analyzed the lungs for biochemical indices of oxidative stress. We found that total lung weight was not altered after treatment, but wet/dry weight ratio decreased 18% ( P < 0.05) and hemoglobin content increased 50% and 36% at 1 and 24 h, respectively. The activity of glucose-6-phosphate dehydrogenase increased significantly, 40% at 1 and 24 h and 84% at 48 h and that of glutathione S-transferases was 60%, P < 0.05 greater at all time points. Lipid peroxidation (estimated by the thiobarbituric acid test) and total protein content increased 3-fold and 2-fold, at 1 and 24 h, respectively. Total and oxidized glutathione contents were significantly elevated, 38% at 1 h and 64% at 24 h for the former and 45% at 24 h and 56% at 48 h for the latter. Because these changes are consistent with the cellular response to oxidative stress, we conclude that BCS injected subcutaneously, can cause changes in the lung possibly via a free radical-mediated mechanism.