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Abstract Objective To investigate the effects of sufentanil on immune response, pain mediators and brain-sparing effect in patients with breast cancer undergoing radical mastectomy. Methods This study was a single center retrospective cohort study. The 118 study subjects were diagnosed and treated in our hospital from the period of January 2020-October 2022, who planned to undergo radical surgery for breast cancer. According to the different surgical drugs, these subjects were divided into sufentanil group and the control group, with 59 cases each. The visual analog scores (VAS) of patients in two groups were compared at 24 hour and 48 hour after surgery. The immune response indexes (including CD3+, CD4+, CD8+, CD4+/CD8+), pain mediators (β-endorphin, substance P and 5-hydroxytryptophan), brain-sparing effect indexes [arterio-venous oxygen content difference (Da-jvO2), jugular bulb venous saturation (S-jvO2), cerebral oxygen uptake (CEO2) and the Mini Mental State Scale (MMSE)], and brain damage indexes [S100 calcium-binding protein B (S100B) and neuron-specific enolase (NSE)] in two groups were compared. The incidence of adverse reactions in two groups was compared. Results VAS scores were obviously lower in the sufentanil group than the control group at 24 hour and 48 hour postoperatively (P