Critically ill hospital patients were fed enteral formulas containing different fat substrates. Seven patients received formula X, which contained 28 g of structured triglycerides and menhaden oil to provide 7.6 g of medium‐chain fatty acids, 2.5 g linoleic acid, 1.3 g eicosapentaenoic acid, and 0.4 g docosahexaenoic acid per 1000 mL of formula. Six patients received formula Y consisting of 36.8 g of medium‐chain triglycerides and corn and soy oils providing 14.3 g medium‐chain fatty acids and 11.7 g linoleic acid per 1000 mL. Feeding of formula X increased plasma total phospholipid levels of eicosapentaenoic acid on days 7 and 14 and docosahexaenoic acid levels on day 14. Plasma levels of linoleic acid were reduced in formula‐X‐fed in comparison to formula‐Y‐fed patients, whereas arachidonic acid was maintained in both groups during feeding. As a result of these changes, the patients receiving formula X had decreased ratios of arachidonic acid:eicosapentaenoic acid in plasma. Formula Y feeding did not alter eicosapentaenoic acid and docosahexaenoic acid levels in the plasma. In the erythrocyte, formula X feeding resulted in a threefold increase in eicosapentaenoic acid from mean baseline levels of 0.4 ± 0.4% to a mean value of 1.2 ± 0.9% at day 7. The formula X feeding decreased linoleic acid levels on days 7 and 14, whereas levels of arachidonic acid and docosahexaenoic acid remained constant. Formula Y feeding did not affect any of the parameters measured for erythrocytes. The ability to alter plasma and erythrocyte levels of n‐3 fatty acids and plasma arachidonic acid:eicosapentaenoic acid ratios may have important implications for patients at risk for sepsis. (Journal of Parenteral and Enteral Nutrition 17:30–34, 1993)