Abstract Objective To analyze the efficacy of surgical resection versus brain biopsy combined with postoperative chemotherapy for primary central nervous system lymphoma (PCNSL) and to discuss a clinically standardized treatment protocol. Methods Patients with a pathological diagnosis of PCNSL and subsequent chemotherapy between 2016 and 2021 at Jiangsu People\'s Hospital were selected and divided into groups according to whether they underwent microsurgical resection or stereotactic needle biopsy. Statistical analyses were performed to compare efficacy and safety in the two groups. Results A total of 21 patients with PCNSL were identified, of whom 12 underwent resection and 9 underwent diagnostic stereotactic biopsy only. Compared with the resection group, the biopsy group had a higher proportion of deep tumors (55.6% vs. 8.3%, P=0.016), and the mean intraoperative bleeding was significantly reduced (13.33 ± 6.61 mL vs. 170.83 ± 101.04 ml, P<0.001). In addition, the mean survival time of patients who died during the postoperative follow-up period was shorter (6.83 ± 1.60 vs. 18.56 ± 10.20 months, P=0.016), and the one-year survival rate was lower (33.3% vs. 83.3%, P=0.032). There was no significant difference between the two groups in terms of the mean progression-free survival time or new functional impairment after surgery. Conclusions For PCNSL, patients who undergo surgical resection have a better outcome than those who undergo biopsy only, suggesting that when the tumor is located at a surgically resectable site, surgical resection should be actively chosen; when the tumor is located at a deep and unresectable site, brain biopsy should be chosen.