Neutrophils have been implicated in the acute formation of gastric mucosal erosions induced by nonsteroidal antiinflammatory drugs. The aims of the present study were to determine, in rats, the role of neutrophils in the pathogenesis of etodolac- and indomethacin-induced gastrointestinal ulceration and blood loss. Both drugs caused gastrointestinal ulceration, which was associated with increased blood loss, a rise in plasma haptoglobin concentration, and a rise in the number of circulating neutrophils. A marked infiltration of neutrophils occurred only in ileal tissue. Pretreatment with a selective antineutrophil serum induced a significant neutropenia, which failed to inhibit either etodolac- or indomethacin-induced gastrointestinal ulceration and blood loss. A further study demonstrated that the antineutrophil serum did not prevent gastric erosions induced by indomethacin, but it inhibited carrageenan paw edema, which is dependent, in part, on neutrophil infiltration and activation. It is concluded that neutrophils do not contribute to gastrointestinal ulceration and blood loss induced by nonsteroidal antiinflammatory drugs. Furthermore, in contrast with previous studies, our results provide no evidence that neutrophils contribute to indomethacin-induced acute gastric erosion formation.