Abstract: Objective: To evaluate the efficacy and safety of PD-1 inhibitor combination therapy for patients with driver gene mutation-negative non-small cell lung cancer (NSCLC) and brain metastases (BMs). Methods: Patients with driver gene mutation-negative NSCLC and BM from The Second Affiliated Hospital of Nanchang University were retrospectively examined from November 2017 to February 2021. All patients received PD-1 inhibitor monotherapy or combination therapy. The primary endpoints were overall survival (OS) and intracranial progression-free survival (iPFS), and the secondary endpoints were safety, intracranial objective response rate (iORR), and intracranial disease control rate (iDCR). Results: Seventy-one patients with driver gene mutation-negative NSCLC and BMs were enrolled; 15 (21.1%) and 56 (78.9%) patients were included in the PD-1 inhibitor monotherapy and combination therapy groups, respectively, with 29 (40.8%) and 27 (38.1%) patients in the combination antiangiogenic therapy and combination chemotherapy groups, respectively. The median follow-up time was 22.6 months; the OS was higher in the combination therapy cohort than in the monotherapy cohort (20.2 months vs. 8.8 months; P=0.032). Subgroup comparisons found that the PD-1 inhibitor+antiangiogenic therapeutic regimen resulted in better OS than the monotherapy regimen (21.7 months vs. 8.8 months, P=0.027). There was no significant difference in grade 3-4 adverse events between the combination therapy and monotherapy groups (P=0.437). No treatment-related deaths or serious life-threatening adverse events were observed in the groups. The multivariate Cox regression analysis revealed that antiangiogenic treatment (P=0.047) was an independent prognostic factor of OS. Conclusions: PD-1 inhibitor combination therapy can significantly improve the OS of patients with driver gene mutation-negative NSCLC and BMs.