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Single institution studies suggest a benefit of a week of preoperative antibiotics prior to percutaneous nephrolithotomy. These studies are limited by lower quality methodology, such as the inclusion of heterogeneous populations or nonstandard definitions of sepsis. The AUA (American Urological Association) Best Practice Statement recommends less than 24 hours of intravenous antibiotics but to our knowledge no other data exist on the duration or benefit of preoperative antibiotics. Using CONSORT (Consolidated Reporting of Trials) guidelines we sought to perform a rigorous multi-institutional trial to assess preoperative antibiotics in patients in whom percutaneous nephrolithotomy was planned and who were at low risk for infection.This randomized controlled trial enrolled patients undergoing percutaneous nephrolithotomy who were at low risk, defined as negative preoperative urine cultures and no urinary drain. Of the subjects 43 were randomized to nitrofurantoin 100 mg twice daily for 7 days preoperatively while a control arm of 43 received no oral antibiotics. All subjects received perioperative doses of ampicillin and gentamicin. Prone percutaneous nephrolithotomy was performed by urologists blinded to randomization. The primary outcome was the development of sepsis.A total of 86 subjects were enrolled. Preoperative patient characteristics were similar in the treatment and control cohorts with a stone size of 19 and 17 mm, respectively (p = 0.47). Intraoperative characteristics also did not differ. The sepsis rate was not statistically different between the treatment and control groups (12% and 14%, respectively, 95% CI –0.163–0.122, p = 1.0). Other infectious parameters and complications were similar, including intensive care admission, fever, hypotension and leukocytosis.Our study demonstrated no advantage to providing 1 week of preoperative oral antibiotics in patients at low risk for infectious complications who undergo percutaneous nephrolithotomy. Perioperative antibiotics according to the AUA Best Practice Statement appear sufficient.