Polymorphoneutrophil leucocytes (PMNLs) are implicated in the pathogenesis of diarrhea-associated hemolytic uremic syndrome (D+ HUS). We investigated mechanisms of PMNL involvement by measuring tumor necrosis factor alpha (TNF alpha) and the novel cytokine, interleukin-8 (IL-8), a potent activator of neutrophils, together with alpha 1- antitrypsin-complexed elastase (alpha 1-AT-E) as a marker of neutrophil degranulation, and anti-neutrophil cytoplasmic antibodies (ANCA). IL-8 was not detected in the 17 normal children, but was significantly elevated in 20 of 25 D+ HUS children (P less than 0.005), and in three of nine children with non-diarrhea-associated (D-) HUS. Sequential data showed that IL-8 peaked transiently in the circulation, reaching a maximum just before a more protracted burst of alpha 1-AT-E. The IL-8 levels correlated significantly with circulating alpha 1-AT-E concentrations (r = 0.50, P less than 0.05). In D+ HUS IL-8 levels also correlated with the PMNL count (r = 0.63, P less than 0.005), and the highest values were seen in those children who died in the acute phase of the disease. TNF alpha was raised in only 1 of 16 D+ HUS children and in no patients were ANCA detected. The data suggest that PMNLs in HUS are recruited by IL-8, that this cytokine plays a key role in the PMNL activation which occurs, and that agents which suppress this recruitment and activation might play a therapeutic role in this disorder.