Linoleic acid (18:2 omega 6), the obligate precursor of arachidonic acid (20:4 omega 6), is an essential nutrient for humans and other mammals. Because arachidonic acid release and metabolism are components of neutrophil activation by certain stimuli, we questioned whether neutrophils depleted of arachidonate as a result of essential fatty acid deficiency might be functionally impaired. We examined this possibility by producing essential fatty acid deficiency in monkeys with lipid-free total parenteral nutrition (TPN). Rhesus and African green monkeys were given calorically equal TPN for up to 23 days with and without a vegetable fat emulsion rich in linoleic acid. Fatty acids were analyzed in total lipid extracts of serum and isolated blood neutrophils by gas-liquid chromatography. Although fatty acids in the serum and neutrophils of monkeys given TPN with lipid did not change, linoleic acid levels decreased by at least 60% in serum and 50% in neutrophils from animals given TPN with no lipid. Moreover, arachidonate levels in neutrophil lipids decreased by at least 50% within 12 days of lipid-free TPN, and the abnormal fatty acid 20:3 omega 9 (characteristic of essential fatty acid deficiency) appeared and steadily increased with time. These biochemical signs of omega 6 fatty acid deficiency were associated with impaired neutrophil function in vitro. Both migration responses and superoxide generation stimulated by N-formyl-methionyl-leucyl-phenylalanine were significantly decreased by 12 days of lipid-free TPN, as was the capacity of activated cells to synthesize leukotriene B4. In contrast, functional responses of fatty acid-deficient neutrophils to leukotriene B4 and phorbol myristate acetate, which have little or no effect on arachidonate release or metabolism, were not significantly altered. These findings indicate that endogenous supplies of arachidonic acid and other essential omega 6 fatty acids influence the functional responsiveness of neutrophils. These studies also indicate that altered neutrophil function is a feature of essential fatty acid deficiency and that it may contribute to the increased risk of infection and decreased inflammatory responses observed in this condition.