Arachidonic acid metabolites and prostaglandins participate in numerous physiologic functions. An enzyme important in the control of prostaglandin production is phospholipase A2. In this study, we have investigated the changes in plasma and hepatic phospholipase A2 activity in diabetes mellitus. In uncontrolled diabetic patients, the postheparin plasma phospholipase A2 level was 18.7 ± 4.1 U/ml; this value was significantly different from the enzyme activities in control subjects (106 ± 9.8 U/ml) and in controlled diabetic patients (87 ± 7.3 U/ml). In the streptozocin-induced diabetic rat model, the postheparin plasma phospholipase A2 level (1.9 ± 0.45 U/ml) was also decreased when compared with normal (9.4 ± 1.6 U/ml) and controlled diabetic rats (7.0 ± 1.3 U/ml). The total hepatic enzyme activity in the uncontrolled diabetic rats was only 21.6% of that seen in control rats. Subcellular fraction studies demonstrated that the enzyme activity is decreased in all fractions in the liver. Liver perfusion studies showed that the heparin-releasable phosholipase A2 activity in the perfusate was significantly decreased in the diabetic rats when compared with control and controlled diabetic animals. We conclude that postheparin plasma and hepatic phospholipase A2 activities are decreased in uncontrolled diabetes mellitus, that the low plasma activity is related to decreased release from the liver, and that the alterations in phospholipase A2 activity in plasma and liver are restored to normal by controlling the diabetic status.