We investigated the association of the uncircumcised foreskin and pyelonephritis in male infants less than 6 months old. During a 21-month prospective study 94 children (age range 2 weeks to 18.9 years) were hospitalized for febrile urinary tract infection. The male-to-female ratio for 35 patients less than 6 months old was 2.2:1. Of 59 patients older than 6 months the male-to-female ratio was reversed at 0.25:1 (p less than 0.001). In 13 of 24 infants (54%) less than 6 months old and in 8 of 12 boys (67%) older than 6 months a dimercaptosuccinic acid renal scan documented acute parenchymal damage (p = 0.72). Vesicoureteral reflux or other genitourinary abnormalities were found in only 3 of 24 patients (12.5%) less than 6 months old compared with 6 of 12 boys (50%) older than 6 months (p = 0.036). Of 24 infants less than 6 months old 22 (92%) were uncircumcised compared with 6 of 12 boys (50%) older than 6 months (p = 0.009). We then retrospectively compared the circumcision status of the infants who had febrile urinary tract infection with a control group of 63 infants matched for age, race and socioeconomic status hospitalized with febrile upper respiratory infection during a similar period. The frequency of uncircumcised infants in the control group with febrile upper respiratory infection was only 44% (28 of 63) compared with 91% of infants with febrile urinary tract infection (p less than 0.001). Overall the findings of the male predominance among patients less than 6 months old with febrile urinary tract infection, the disproportionately high frequency of infants with febrile urinary tract infection who were not circumcised, and the disproportionately low occurrence of vesicoureteral reflux and other genitourinary abnormalities in infants with febrile urinary tract infection strongly support an association between circumcision status and the risk for febrile urinary tract infection and pyelonephritis in male infants.