The lethal effect of sulfur mustard on L-cells was reduced by pretreating the cells with dithiothreitol (DTT), aminoethylisothiuronium bromide, mercaptoethylamine, and some alkyl derivatives of this compound. The disulfides of these agents were without protective activity. The protective mechanism by which DTT operated involved a simple inactivation of the sulfur mustard. This deduction was based on the finding that alkylation by mustard of cellular DNA, RNA, and protein was reduced by DTT treatment in parallel with the reduction in toxicity of the mustard. DTT at a tolerated dose of 100 mg/kg provided scant protection to mice against the nitrogen mustard HN2.