We investigated the enhancing effect of three alkyo-2-pyrrolidones on transdermal penetration of phenolsulfon-phthalein (phenol red) and indomethacin from an aqueous vehicle by using an in vitro technique with excised rat skin. The enhancers included 1-methyl- (I), 1-hexyl- (II) and 1-lauryl-2-pyrrolidone (III). These derivatives effectively enhanced the penetration and skin accumulation of phenol red and indomethacin. Lipophilic enhancers such as II and III showed particularly high enhancing effects. The penetration profiles of phenol red and indomethacin showed a lag phase followed by a linear increase. Compounds II and II showed long lag times. The enhancer penetration was also determined. Compounds I and II showed a slight penetration. Compound III showed little penetration but high skin accumulation.