AIM: To investigate the effect of BCG + piroxicam versus BCG + gemcitabine in the prevention of postoperative recurrence in intermediate- to high-risk bladder cancer and the effect on serum albumin/globulin ratio (AGR) and paraoxonase 1 (PON1). METHODS: Eighty patients with medium-high risk bladder cancer in our hospital from October 2021 to April 2022 were randomly divided into two groups with 40 cases each. Both groups received transurethral resection of bladder tumor. The control group received postoperative bladder perfusion of pirubicin combined with BCG vaccine, and the study group received postoperative bladder perfusion of gemcitabine combined with BCG vaccine. The therapeutic effect, serum tumor markers ［secretory protein Dickkopf (DKK), bladder cancer specific nuclear matrix protein-1 (BLCA-1), β2-microglobulin (β2-MG)］, new angiogenesis factors ［vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF)］, AGR and PON were compared between the two groups 1. Level, quality of life ［Core Quality of Life Questionnaire Scale (EORTC QLQ-C30)］, functional status ［Functional status Scoring Scale (KPS)］, adverse reactions, The recurrence rates at 1 year after surgery were compared between the two groups. RESULTS: The total effective rate of the study group was 92.50%(37/40) higher than that of the control group 75.00%(30/40) (P<0.05). The serum levels of DKK, BLCA-1, β2-MG, VEGF, FGF and AGR in the study group were lower than those in the control group at 1 month, 3 months and 6 months after surgery, while the level of PON1 was higher than that in the control group (P<0.05). The EORTC QLQ-C30 and KPS scores of the study group were higher than those of the control group at 1, 3 and 6 months after surgery (P<0.05). The incidence of nausea/vomiting, diarrhea, leukopenia and cystitis in the study group was lower than that in the control group (P<0.05). The recurrence rate of the study group 1 year and 2 years after surgery was lower than that of the control group (P<0.05). CONSLUSION: Compared with pirubicin combined with BCG vaccine, gemcitabine combined with BCG vaccine is more effective in the treatment of middle and high-risk bladder cancer, which can inhibit tumor angiogenesis, regulate AGR and PON1 levels, prevent postoperative recurrence, improve quality of life, improve functional status, and have higher safety.