Background. Infection-related urolithiasis is associated with high recurrence rates due to persistent bacterial colonization and biofilm formation, which limit the effectiveness of standard systemic antimicrobial therapy. Additional local preventive strategies are required to improve postoperative outcomes. Objective. To evaluate the effectiveness of intrapelvic administration of dioxidine in reducing recurrence rates and improving microbiological eradication in patients with infection-related urolithiasis after percutaneous nephrolithotripsy (PCNL). Materials and Methods. A total of 268 patients with infection-related urolithiasis who underwent PCNL were included in this study. Patients were divided into two groups: a control group (n = 130) receiving standard prophylaxis and a main group (n = 138) receiving additional intrapelvic dioxidine instillation via a nephrostomy drain in the early postoperative period. Patients were followed for 24 months. Primary endpoints included recurrence rate and recurrence-free survival; secondary endpoints included microbiological eradication, bacteriuria, and antibiotic resistance. Statistical analysis was performed using appropriate comparative methods. Results. During the 24-month follow-up, recurrence was observed in 26.2% of patients in the control group and 11.6% in the main group (p = 0.002). The odds ratio for recurrence was 2.72 (95% CI: 1.45–5.10). The number needed to treat was 7. Microbiological eradication was achieved in 44.6% of control patients and 63.8% of main group patients (p = 0.002), with an odds ratio of 2.18 (95% CI: 1.33–3.57). The effect was sustained and associated with suppression of persistent infection. Conclusion. Intrapelvic administration of dioxidine significantly reduces recurrence of infection-related urolithiasis and improves microbiological outcomes, representing an effective adjunct to standard postoperative prophylaxis.