Background: Although multiple single-arm clinical trials have shown promising pathologic complete response (pCR) rates with neoadjuvant ICIs combined with gemcitabine plus cisplatin in MIBC, lymph node‐positive bladder cancer is generally excluded. In this study, our specific aim was to compare the efficacy and prognosis of neoadjuvant tislelizumab combined with gemcitabine plus cisplatin in patients with lymph node‐positive bladder cancer. Methods: In this investigator-initiated study, eligible patients had cT2-T4 N+ M0 MIBC, cisplatin-eligible, and to be planned radical cystectomy (RC). Patients received tislelizumab 200 mg in day 8 (D8), cisplatin 70 mg/m2 D2-4, and gemcitabine 1000 mg/m2 D1 and D8 every 21 days for 3 or 4 cycles. RC was performed within 6 weeks after last dose treatment. The primary endpoint was pathologic complete response (pCR, ypT0). Secondary endpoints included pathologic downstaging (<ypT2), EFS, OS and safety. Results: A total of 15 pts were enrolled,14 pts (2 cT2, 7 cT3, 5 cT4) have completed neoadjuvant therapy and underwent RC. One patient declined surgery for personal reasons and received further systemic therapy. In 14 pts evaluable for efficacy, the investigator-assessed confirmed clinical complete response was 21.4% (3/14). Final pathologic results showed that 5 pts (50%) achieved pCR (ypT0N0), 4 ypT1, and 5 ypT2/T3, and 9 patients (<ypT2N0,64.2%) had staging downgrades, with no patients experiencing progression. A complete nodal response (pN0) occurred in 11 (78.5%) pts after tislelizumab +chemotherapy. The median follow-up was 8.9 months, with one death due to multiple metastases and the remaining patients showing no signs of recurrence or metastasis. Median EFS and OS was not reached. Most common neoadjuvant therapy-related AEs of any grade were hematologic toxicities (11/14,78.5%), nausea (9/14,64.2%), vomiting (8/14,57.1%). Grade ≥3 neoadjuvant therapy-related AEs were neutropenia (n = 3), thrombocytopenia (n = 2), anemia (n = 2). One patient discontinued tislelizumab due to AEs. Conclusions: The combination of tislelizumab and gemcitabine/cisplatin is clinically active with a manageable safety profile as a neoadjuvant therapy for lymph node‐positive bladder cancer. Clinical trial information: NCT04570410.