Six experiments were conducted to determine the influence of an essential fatty acid deficient diet (EFAD), and various levels of dietary polyunsaturated fatty acids, on humoral immunity in mice. The results indicated that: 1) Consumption of diets deficient in essential fatty acids (0% corn oil) significantly reduced the humoral response. This reduction was demonstrated after feeding the essential fatty acid deficient diet for only 28 days; and preceded the effects of essential fatty acid deficiency on growth or appearance. 2) Reduced antibody response was demonstrated against T-cell dependent and T-cell independent antigens, and in both primary and secondary responses of mice fed the essential fatty acid deficient diet. 3) After 56 days of feeding the EFAD diet (0% corn oil), mice switched to the control diet (13% corn oil) for 7 days demonstrated full recovery of the humoral response. 4) Diets containing various levels of polyunsaturated fatty acids (from 2 to 70% of energy from corn oil) did not adversely affect the humoral response. The results support the hypothesis that essential fatty acids play a crucial role in maintaining the functional integrity of humoral immunity.