The natural antioxidant ergothioneine (2-mercaptohistidine trimethylbetaine) is a fungal metabolite and found in most plant and animal tissues. The effect of ergothioneine on diabetic embryopathy in rats was assessed. Supplementation of diabetic pregnant rats with L-ergothioneine (1.147 mg/kg body weight) daily for the first 11.5 days of pregnancy reduced the rate of embryo malformations, to values similar to the non-diabetic animals. The ergothioneine had no effect on the plasma glucose levels, both in diabetic and control animals. We conclude that the inhibition of the glucose-mediated free radical dependent embryo malformation by ergothioneine is an important antioxidant prophylactic mechanism, which when combined with vitamin E could benefit the management of diabetic embryopathy.