Background and Objectives: Patients undergoing cystoscopy can experience discomfort or pain during the procedure. In some cases, a urinary tract infection (UTI) with storage lower urinary tract symptoms (LUTS) may occur in the days following the procedure. This study aimed to assess the efficacy of D-mannose plusSaccharomyces boulardiiin the prevention of UTIs and discomfort in patients undergoing cystoscopy.Materials and Methods: A single-center prospective randomized pilot study was conducted between April 2019 and June 2020. Patients undergoing cystoscopy for suspected bladder cancer (BCa) or in the follow-up for BCa were enrolled. Patients were randomized into two groups: D-Mannose plusSaccharomyces boulardii(Group A) vs. no treatment (Group B). A urine culture was prescribed regardless of symptoms 7 days before and 7 days after cystoscopy. The International Prostatic Symptoms Score (IPSS), 0–10 numeric rating scale (NRS) for local pain/discomfort, and EORTC Core Quality of Life questionnaire (EORTC QLQ-C30) were administered before cystoscopy and 7 days after.Results: A total of 32 patients (16 per group) were enrolled. No urine culture was positive in Group A 7 days after cystoscopy, while 3 patients (18.8%) in Group B had a positive control urine culture (p= 0.044). All patients with positive control urine culture reported the onset or worsening of urinary symptoms, excluding the diagnosis of asymptomatic bacteriuria. At 7 days after cystoscopy, the median IPSS of Group A was significantly lower than that of Group B (10.5 vs. 16.5 points;p= 0.021), and at 7 days, the median NRS for local discomfort/pain of Group A was significantly lower than that for Group B (1.5 vs. 4.0 points;p= 0.012). No statistically significant difference (p> 0.05) in the median IPSS-QoL and EORTC QLQ-C30 was found between groups.Conclusions: D-Mannose plusSaccharomyces boulardiiadministered after cystoscopy seem to significantly reduce the incidence of UTI, the severity of LUTS, and the intensity of local discomfort.