Since its introduction into the endourologist's armamentarium almost 40 years ago, percutaneous nephrolithotomy (PCNL) has become the standard of care for patients with large-volume nephrolithiasis. Postoperative infection is one of the most common complications of the procedure, and postoperative sepsis is one of the most detrimental. A number of factors have been found to increase the risk of postoperative sepsis. These include patient characteristics that are known preoperatively, such as urine culture obtained from the bladder or from the renal pelvis if percutaneous access to the renal pelvis is obtained in advance to the procedure. Neurogenic bladder dysfunction secondary to spinal cord injury and anatomical renal abnormalities, such as pelvicalyceal dilatation, have also been associated with increased incidence of fever and sepsis after the procedure. Several intraoperative factors, such as the average renal pressure sustained during PCNL and the operative time, also seem to increase the risk of sepsis. Finally, the contribution of postoperative factors, such as presence of a nephrostomy tube or a urethral catheter, has also been investigated. A short preoperative course of antibiotics has been found to significantly decrease the rate of postoperative fever and sepsis. Novel agents targeted at sepsis prevention and treatment, such as anti-endotoxin antibodies and cholesterol-lowering drugs statins, are currently under investigation.