To determine whether severity of the prodromal gastrointestinal illness is associated with the course and complications of the extraintestinal manifestations of hemolytic-uremic syndrome, we conducted a retrospective review of children (n = 509) hospitalized with hemolytic-uremic syndrome. Those who came to the hospital with colitis and rectal prolapse associated with hemolytic-uremic syndrome (group I, n = 40) were compared with an equal number of time-matched children with hemolytic-uremic syndrome but without prolapse (group II). Children in group I had evidence of more severe colitis than children in group II had, as indicated by increased frequency of bloody diarrhea (p less than 0.001) and longer duration of diarrhea (p less than 0.001). However, they also had more severe extraintestinal manifestations during hemolytic-uremic syndrome, including edema (p less than 0.0001), severe thrombocytopenia (p less than 0.0001), prolonged anuria (p less than 0.001), and seizures (p = 0.036). Long-term prognosis for recovery of renal function was worse for group I than group II. Within group II, patients with bloody diarrhea had milder extraintestinal illness than those with prolapse but more severe extraintestinal illness than those with watery diarrhea. Analysis of Kaplan-Meier survival curves demonstrated a better prognosis for return of normal renal function in the children with watery diarrhea but without prolapse (p = 0.009) than in children with bloody diarrhea or prolapse. These data demonstrate that the severity of the gastrointestinal prodrome reflects the severity of the extraintestinal acute microangiopathic process and the resulting long-term outcome. Widespread vascular damage, often followed by permanent sequelae, is characteristic of patients with the most severe colitis.