Certain deleterious effects of cyclophosphamide, for example urotoxicity, can be prevented by the administration of thiol compounds such as 2-mercaptoethane sulfonate (MESNA) without altering the therapeutic efficacy of cyclophosphamide. To evaluate the effect of MESNA on the teratogenicity of cyclophosphamide, pregnant Sprague-Dawley rats were divided into nine treatment groups. Individual groups were administered 0.9% NaCl or cyclophosphamide (10 or 15 mg/kg) alone or in combination with MESNA at one of two doses (5 or 30 mg/kg) on Day 13 of gestation. The fetuses were examined for malformations on Day 20 of gestation. Cyclophosphamide alone produced malformations in 50% (10 mg/kg) or 100% (15 mg/kg) of the fetuses. The abnormalities observed were hydrocephaly, hind- and forelimb defects, open eyes, cleft palate, edema, micrognathia, omphalocele, and various skeletal defects. MESNA alone did not induce a significant number of fetal malformations compared to control. The low dose of MESNA had no significant effect on the total incidence of external malformations produced by either dose of cyclophosphamide. The high dose of MESNA significantly reduced the total number of externally abnormal fetuses and fetuses with skeletal defects produced by both 10 and 15 mg/kg of cyclophosphamide. This protection, although statistically significant (p less than or equal to 0.05), is probably not extensive enough for MESNA to be considered effective in protecting pregnant women from the teratogenic effects of cyclophosphamide chemotherapy.