Defective regulation of neutrophil chemotaxis occurs in patients with alcoholic liver disease. One potent mediator of neutrophil chemotaxis is the complement-derived neutrophil chemoattractant, C5a, which can be inhibited by a serum protein, chemotactic factor inactivator. We hypothesized that chemotactic factor inactivator elevation might, in part, explain the defective neutrophil chemotaxis seen in patients with alcoholic hepatitis. To test this hypothesis, sera were collected from 22 patients with alcoholic hepatitis and 9 normal controls, and evaluated for the antigenic presence of chemotactic factor inactivator using an ELISA test. Chemotactic factor inactivator levels were found to be markedly elevated in patients with alcoholic hepatitis (162 f 24 pg per ml) compared to normals (60 f 3 pg per ml, p c 0.01). Subdividing the hepatitis patients revealed that the elevation of chemotactic factor inactivator was found to be greatest in those patients with mild alcoholic hepatitis (prothrombin time within normal limits and bilirubin 55 mg per dl, 256 2 44 pg per ml, p c 0.001), while the group with the severest hepatic dysfunction (prolonged prothrombin time and bilirubin >5 mg per dl) did not differ significantly from controls (71 2 11 pg/ml, p c 0.2). Importantly, the inhibition of C5a-induced chemotactic activity by partially purified chemotactic factor inactivator correlated with antigenic amounts of chemotactic factor inactivator in serum (r = 0.63, p c 0.05). The C5a inhibitory activity in sera obtained from patients with alcoholic hepatitis coprecipitated with chemotactic factor inactivator when serum was precipitated by ammonium sulfate precipitation (45 to 64% saturation). Depleting chemotactic factor inactivator by affinity chromatography resulted in a major loss of the ability of this partially purified chemotactic factor inactivator to inhibit C5a-induced chemotaxis (50 vs. 26% inhibition, p c 0.001), suggesting that chemotactic factor inactivator is a major inhibitor of C5a in these patients. These data suggest that elevations in chemotactic factor inactivator may explain impaired neutrophil chemotaxis in patients with alcoholic hepatitis.