Deficiency of essential fatty acid (EFA) containing linoleic acid (18:2n-6) in humans or animals induces morphologic changes characterized by severe scaly dermatosis, extensive percutaneous water loss, and hyperproliferation of the epidermis. Microscopically, the epidermis is characterized by hyperkeratosis and acanthosis. The refeeding of safflower oil containing linoleic acid or primrose oil (containing linoleic acid [18:2n-6] and gamma-linolenic acid [18:3n-6]) acids to EFA-deficient guinea pigs reverses the EFA-deficiency symptoms. In contrast, replacement of safflower oil with menhaden fish oil, (containing eicosapentaenoic acid [20:5n-3] and docosahexaenoic acid [22:6n-3]) did not reverse the symptoms of EFA deficiency. These results indicate: (1) that an understanding of the roles of vegetable or fish oil in skin must evolve from an understanding of the roles of each constituent n-6 or n-3 fatty acid, and (2) that the n-3 fatty acids may function to modulate the metabolism and function of the n-6 fatty acids in vivo.