We investigated preliminary acute toxicity and primary skin irritation of nine pyrrolidone derivatives which had been previously developed as transdermal penetration enhancers. The acute toxicity was observed at a dose of 500 mg/kg after intraperitoneal administration in mice. Their primary skin irritations were examined with rabbit dorsal skin. 1-Lauryl-2-pyrrolidone induced the most severe irritation among the derivatives. Pyrrolidone derivatives having methyl group and methyloxycarbonyl group caused little irritation. The primary irritation indices of pyrrolidone derivatives were not relative to their accumulations in the skin but to their enhancing effects. In conclusion, 1-hexyl-4-methyloxycarbonyl- and 1-lauryl-4-methyloxycarbonyl-2-pyrrolidone are suggested to be adequate enhancers, judging from the balance of their enhancing activity and irritation.