To assess the efficacy and tolerability of D-mannose-containing product (Cystoman(®)) in preventing recurrence in patients who underwent surgical treatment for infection related urinary stones. From January 2011 to February 2013 we have enrolled all consecutive patients affected by staghorn calculi and recurrent urinary tract infections (UTIs). All patients recommended for surgery were scheduled for percutaneous nephrolithotomy. The study agent was administered daily for 5 months after surgical procedure. At baseline and 5-month follow-up all patients underwent abdominal Computed Tomography (CT) scan and they also completed Medical Outcomes Study short-form, 36-item questionnaire (SF-36). They performed urine and urine culture monthly. The primary endpoints were the assessment of the efficacy with regard to infection-related urinary stone recurrence and the tolerability of Cystoman(®). The secondary endpoint was the evaluation of quality-of-life symptoms. During the study period, a total of 27 patients were included in the study. The data from 25 patients were analyzable. Seventeen patients (68%) did not report UTIs during follow-up. Eight patients (32%) remained infected and the average number of UTIs was 2.6 ± 1.6 in 5 months. At 5-month follow-up 17 (68%) patients were free from stones recurrence; in 8 (32%) cases CT scan revealed stone recurrence with an average stone diameter of 1.1 ± 0.4 cm. In nonrecurring patients, 2 (11.7%) reported an average of 1.5 ± 0.7 UTIs episodes; in recurring patients, 6 (75%) showed 3 ± 1.67 of UTIs episodes. Statistically significant differences were seen in the occurrence of UTIs episodes were detected between nonrecurring stone patients and recurring patients (p < 0.05). Moreover, statistically significant changes were detected in SF-36 scores from baseline to month 5 in the categories of physical functioning and energy/fatigue (p < 0.05). Cystoman(®) is effective in preventing infection-related urinary stones.