Essential fatty acid (EFA) deficient rodents demonstrate abnormal epidermal permeability barrier function and differentiation, defects which can be corrected by either topical or systemic administration of linoleic acid. Since linoleic acid is a precursor of prostaglandins, correction of the defect in barrier function may either reflect a prostaglandin-mediated return toward normal epidermal differentiation, or, instead, a direct effect of linoleic acid. To test these possibilities severely EFA-deficient mice were pretreated daily with indomethacin and/or 5,8,11,14-eicosatetrayeonic acid, and then placed on normal (lineolic acid-supplemented) diets. Endogenous formation of prostaglandin E2 was determined by thin-layer chromatography after transformation into prostaglandin B2 with ethanolic-hydrochloric acid. Animals treated with both indomethacin and TYA DEMONSTRATED SUBSTANTIAL REDUCTIONS IN PROSTAGLANDIN E2 levels in liver and skin. Animals replenished with linoleic acid invariably demonstrated a rapid return of barrier function toward normal whether or not they were blockaded, while nonreplenished animals, with or without inhibition of prostaglandin biosynthesis, demonstrated continued deterioration in barrier function. In other experiments, topically applied linoleic acid rapidly reversed the defect in barrier function at the sites of application prior to systemic correction of the EFA deficient state. These results suggest that: (1) defective cutaneous barrier function in EFA deficiency can be corrected locally without prior systemic reversal of the deficiency state; and (2) that linoleic acid may play a direct role in the epidermal permeability barrier independent of its role in prostaglandin metabolism.