Background: Due to ongoing bacillus Calmette-Guerin (BCG) shortages, sequential intravesical gemcitabine and docetaxel (Gem/Doce) has been increasingly utilized as first-line adjuvant treatment for patients with high-risk non-muscle invasive bladder cancer. Herein, we compared oncologic outcomes and tolerance of Gem/Doce versus BCG. Methods: We retrospectively identified 312 patients with high-risk, treatment-naïve, NMIBC treated at our institution between January 2011 and December 2021; 174 treated with BCG and 138 treated with Gem/Doce. After complete TURBT, patients received a 6 weekly intravesical induction regimen of Gem/Doce or BCG, followed by maintenance if disease free at first follow-up. The primary outcome was high-grade (HG) recurrence-free survival (RFS). Cox multivariable regression analyses were performed. Adverse events were reported using CTCAE v5. Results: Median follow-up for patients receiving Gem/Doce and BCG was 23 and 49 months, respectively. Baseline clinicopathologic characteristics were similar between groups, including presence of CIS (41% vs 44%, p=0.6) and T1 (37% vs 41%, p=0.5) disease for patients receiving Gem/Doce and BCG, respectively. HG-RFS estimates at 6, 12, and 24-months were 92%, 85%, and 81% for Gem/Doce and 76%, 71%, and 69% for BCG, respectively. On multivariable Cox regression analyses controlling for age, gender, treatment year, and presence of CIS, Gem/Doce treatment was associated with superior HG-RFS (HR 0.57, p=0.04) and RFS (HR 0.56, p=0.02) versus BCG (Table). Progression-free, cystectomy-free, cancer-specific, and overall survival were similar between groups. Induction BCG was associated with greater treatment discontinuation (9.2% vs 2.9%, p=0.02), dysuria (p=0.03), and arthralgias (p=0.02), but less bladder spasms (p<0.01) than Gem/Doce, respectively. Conclusions: In the setting of ongoing BCG production shortages, we found Gem/Doce to be an efficacious and well-tolerated alternative first-line therapy for high-risk NMIBC. Prospective randomized evaluation is being planned.