Background: To evaluate the efficacy and safety of tislelizumab combined with gemcitabine and cisplatin as neoadjuvant therapy for patients (pts) with clinical T2-T4aN0M0 (cT2-T4aN0M0) muscle-invasive bladder urothelial cancer (MIBC). Methods: This multicenter, open-label, single arm phase II study enrolled pts tolerated with the cisplatin therapy. Eligible pts received tislelizumab 200 mg in day 1 (D1), cisplatin 70 mg/m² D2, and gemcitabine 1000 mg/m² D1 and D8 every 21 days for four cycles. Radical cystectomy (RC) was performed within 6 weeks after last dose treatment. The primary end point was pathologic complete response (pCR, pT0N0M0). Secondary end points were pathologic downstaging (≤pT1N0M0), EFS, OS and safety. Simon two-stage design was used. If > 5 pts achieved pCR in the first stage (n = 22), study would proceed to the second stage and enroll 33 additional pts. If > 18 of 55 pts achieved pCR, we would deem the study to have met the primary endpoint. Results: We reported the results in the first stage. By Oct 2021, 23 eligible pts were enrolled. Eighteen pts have completed neoadjuvant therapy, with median age of 62 (48-72) years and 8 (44.4%) pts of PD-L1 positive, among whom 17 pts underwent RC and one declined RC. At the data cut off time of 14^th Jan 2022, among 17 evaluable pts (12 cT2, 3 cT3, and 2 cT4a), 10 (58.8% [95% CI, 32.9-81.6]) pts achieved pCR and 13 (76.5% [95% CI, 50.1-93.2]) achieved pathologic downstaging. No significant differences were found in pCR (62.5% vs. 55.6%) and downstaging (75.0% vs. 77.8%) rates between pts with PD-L1 positive versus PD-L1 negative. Eighteen pts completed 71/72 cycles of tislelizumab, 68/72 cycles of cisplatin and 135/144 cycles of gemcitabine therapy. The rate of dose reduction (all due to AEs) of cisplatin and gemcitabine therapy was 25.0% (17/68 cycles) and 23.7% (32/135 cycles), respectively. The relative dose intensity of tislelizumab, cisplatin and gemcitabine were 93.6%, 84.5% and 85.9%, respectively. Most common neoadjuvant therapy related AEs of any grade were hematologic toxicities (94.4%), nausea (72.2%), vomiting (61.1%), decreased appetite (55.6%), fatigue (27.8%), pruritus (22.2%) and ALT/AST increased (22.2%). Grade ≥3 neoadjuvant therapy related AEs were neutropenia (n = 6), thrombocytopenia (n = 4), anemia (n = 2) and lymphocyte count decreased (n = 1). Eight pts experienced grade 1-2 immune related AEs, including pruritus (n = 4), rash (n = 2), ALT/AST increased (n = 4), GGT increased (n = 2), CPK increased (n = 1), hyperthyroidism (n = 1), hypothyroidism (n = 1). Conclusions: Neoadjuvant tislelizumab combined with gemcitabine and cisplatin showed promising anti-tumor activity with high pCR and well tolerance in MIBC pts. The target of first stage has been achieved, and enrollment is ongoing. At the data cut off 14^th Jan 2022, 34 pts have been enrolled. Clinical trial information: ChiCTR2000037670.