Indomethacin sodium promotes closure of the patent ductus arteriosus in premature infants. In addition to renal and gastrointestinal side effects, indomethacin may predispose to infection because of inhibition of polymorphonuclear leukocyte (PMN) function. We retrospectively assessed the incidence of sepsis in a group of 58 premature infants with patent ductus arteriosus who received either oral indomethacin, surgery, or usual medical management. A significant increase in the incidence of sepsis was observed in the indomethacin-treated group compared with patients treated with surgery or usual medical management (seven of 31 vs one of 27). All episodes of sepsis occurred within one week of therapy. Patients in the indomethacin group who developed sepsis were less mature, had more gastrointestinal symptoms, and were less likely to survive than nonseptic indomethacin-treated patients. Nine patients studied prospectively showed no difference in PMN chemotaxis and adherence before and after indomethacin administration. Neither adult nor neonatal cord PMN chemotaxis was inhibited following in vitro incubation with concentrations of indomethacin ranging from 1 to 1000 mg/L. Bactericidal activity of neonatal cord neutrophils was also unaffected by concentrations of indomethacin from 1 to 200 mg/L. These results suggest that oral indomethacin administration may predispose the very-low-birth-weight infant to the development of sepsis shortly after therapy is begun although the mechanism remains unclear.