Introduction Granulocyte colony-stimulating factor (G-CSF) is routinely used to manage chemotherapy-induced neutropenia in patients receiving chemoimmunotherapy for advanced non-small cell lung cancer (NSCLC). However, its potential to promote immunosuppressive tumor-associated neutrophils (TANs) has raised theoretical concerns about compromising the efficacy of immune checkpoint inhibitors (ICIs). We aimed to evaluate the real-world association between G-CSF use and survival outcomes in this setting.Methods In this retrospective cohort study, we analyzed data from patients with unresectable, locally advanced or metastatic NSCLC who initiated first- or later-line chemoimmunotherapy at a tertiary academic center between 2018 and 2021. Multivariable Cox regression and inverse probability of treatment weighting (IPTW) were used to adjust for key prognostic confounders.Results Among 120 enrolled patients, 57 (47.5%) received G-CSF during treatment. With a median follow-up of 22.6 months, the median progression-free survival (PFS) was 12.9 months in the G-CSF group versus 9.6 months in the non-G-CSF group (hazard ratio [HR] = 0.97, 95% CI: 0.60-1.58; P = 0.92). The median overall survival (OS) was 17.6 versus 15.3 months, respectively (HR = 0.99, 95% CI: 0.50-1.98; P = 0.99). In multivariable analysis, G-CSF administration was not independently associated with PFS (adjusted HR [aHR] = 1.08, 95% CI: 0.60-1.93; P = 0.80) or OS (aHR = 1.96, 95% CI: 0.80-4.78; P = 0.14). IPTW-adjusted analyses confirmed these null associations (PFS: HR = 1.30, P = 0.85; OS: HR = 1.00, P = 0.95).Discussion In this real-world cohort, no statistically significant association between G-CSF use and survival outcomes was observed among patients with advanced NSCLC treated with chemoimmunotherapy. Further prospective studies are warranted to better define the potential risks and benefits of G-CSF in this setting, particularly regarding its long-term association with survival outcomes.