PURPOSE: To compare intravesical instillation of gemcitabine and anthracyclines in the treatment of primary non-muscle-invasive bladder cancer (NMIBC), and to evaluate the effect of changing intravesical chemotherapy drugs on the the second recurrence of NMIBC. METHOD: Patients with NMIBC who underwent transurethral resection of bladder tumor (TURBT) for the first time in our center from January 2014 to December 2023 were enrolled. Kaplan-Meier method was used to analyze the recurrence-free survival (RFS) and progression-free survival (PFS), and COX regression was used to analyze the risk factors for recurrence. RESULT: 464 patients were included in the study (212 in the gemcitabine group and 252 in the anthracyclines group). Anthracyclines-treated patients had superior RFS compared to gemcitabine-treated patients (p = 0.006), but PFS did not differ significantly between the two groups (p = 0.654). After the first recurrence of NMIBC, patients who changed intravesical chemotherapy drugs had better RFS than those who kept the original chemotherapy drugs (p = 0.037). In terms of safety, the incidence of adverse events of pirarubicin was significantly higher than that of gemcitabine and epirubicin (55.2% vs 26.4% vs 36.2%, p <
0.001). CONCLUSION: Anthracyclines are more effective than gemcitabine in preventing recurrence of primary NMIBC but with more adverse events. After the first recurrence of NMIBC, changing the drugs of intravesical chemotherapy can reduce the second recurrence of NMIBC.