The purpose of this study was to compare the treatment outcomes of staghorn stones using minimally invasive percutaneous nephrolithotomy (MPCNL) in patients who had positive preoperative urine culture to patients with negative urine culture. The records of 284 patients with staghorn calculi, who underwent MPCNL in our center from January 2012 to January 2013, were retrospectively analyzed. Patients were divided into positive and negative group, according to the result of preoperative urine culture. Staghorn stones with negative culture received a single dose of broad spectrum antibiotic prophylaxis, whereas stones with positive culture were treated for at least 72 h according to antibiogram. The perioperative findings and postoperative outcomes were compared between the two groups. There were 70 (24.6%) patients with positive and 214 (75.4%) patients with negative preoperative urine culture who underwent MPCNL. There were no statistical differences in the duration of hospital stay, operative time, estimated blood loss, final stone free rate (SFR) as well as the incidence of the following infectious complications such as fever, systemic inflammatory response syndrome and septic shock, between both groups. Our retrospective study showed that MPCNL was a safe and effective modality in the treatment of staghorn stones. The morbidity, complication, and SFR were similar between patients with positive and negative preoperative urine cultures, once the culture positive infections were adequately controlled.