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Introduction: In this study, we aimed to explore using the predictive role of systemic immune inflammation index (SII) for responses of intravesical Bacillus Calmette-Guérin (BCG) therapy in patients with intermediate- and high-risk non-muscle-invasive bladder cancer (NMIBC). Methods: From 9 centers, we reviewed the data of patients treated for intermediate- and high-risk NMIBC between 2011 and 2021. All patients enrolled in the study presented with T1 and/or high-grade tumors on initial TURB had undergone re-TURB within 4–6 weeks after initial TURB and had received at least a 6-week course of intravesical BCG induction. SII was calculated with the formula SII = (P × N)/L, where P, N, and L refer to peripheral platelet, neutrophil, and lymphocyte counts, respectively. In patients with intermediate- and high-risk NMIBC, the clinicopathological features and follow-up data were evaluated to compare SII with other systemic inflammation-based prognostic indices. These included the neutrophil-to-lymphocyte ratio (NLR), platelet-to-neutrophil ratio (PNR), and platelet-to-lymphocyte ratio (PLR). Results: A total of 269 patients were enrolled in the study. Median follow-up time was 39 months. Disease recurrence and progression were observed in 71 (26.4%) and 19 (7.1%) patients, respectively. For groups with and without disease recurrence in terms of NLR, PLR, PNR, and SII calculated prior to intravesical BCG treatment, no statistically significant differences were observed (p = 0.470, p = 0.247, p = 0.495, and p = 0.243, respectively). Moreover, there were also no statistically significant differences between the groups with and without disease progression in terms of NLR, PLR, PNR, and SII (p = 0.504, p = 0.165, p = 0.410, and p = 0.242, respectively). SII did not show any statistically significant difference between early (<6 months) and late (≥6 months) recurrence (p = 0.492) and progression groups (p = 0.216). Conclusion: For patients with intermediate- and high-risk NMIBC, serum SII levels do not present as an appropriate biomarker for the prediction of disease recurrence and progression following intravesical BCG therapy. A possible explanation for the failure of SII to predict BCG response may be found in the impact of Turkey's nationwide tuberculosis vaccination program. [ABSTRACT FROM AUTHOR]