Background: Percutaneous nephrolithotomy (PCNL) is commonly used in the treatment of large renal stones. Postoperative infections are a common consequence of these procedures. Objectives: The purpose of this study is to evaluate the effects of antibiotic therapy before PCNL on the possibility of developing fever and common complications after the procedure. Methods: We carried out a retrospective cross-sectional study involving 708 patients who had undergone PCNL at Razi Hospital in Rasht, covering the period from 2012 to 2022. Patients were allocated into two groups: Group 1 included 454 patients who had received antibiotic therapy, and group 2 included 254 patients who had not received pre-operative antibiotic therapy. Results: In group 1, there were 241 males (53.1%) and 213 females (46.9%), while in group 2, there were 138 males (54.3%) and 116 females (45.7%). In group 1, 82.7% of patients treated with antibiotics had a negative culture. The hospitalization time was 4.00 ± 1.75 days for group 1 and 2.26 ± 1.56 days for group 2. Fever was observed in 39 patients (11.2%) in group 1. Sepsis was seen in only one patient (0.3%) in group 1. There is a significant relationship between total hospitalization time (P = 0.000), hospitalization after the operation (P = 0.000), hypertension (P = 0.009), ischemic heart disease (P = 0.050), history of shock wave lithotripsy (P = 0.003), hydronephrosis (P = 0.000), age (P = 0.004), and hemoglobin levels (P = 0.000) with antibiotic therapy. Conclusions: Surgeon overprescription of antibiotics may lead to resistance, complicating outcomes and extending hospital stays after PCNL. Some complications remain unaffected by antibiotic therapy due to surgical experience.