Background: Although brain metastases (BM) at diagnosis are common in non-squamous NSCLC patients (ns-NSCLC), they have been mostly excluded from randomized trials. The aim of this retrospective study was to evaluate real-word outcomes of frontline immune checkpoint inhibitor (ICI) in these patients. Methods: We conducted a retrospective study to assess the intracranial and overall efficacy of first-line ICI-based therapy compared to chemotherapy (CT) in ns-NSCLC patients diagnosed with BM, showing no targetable alterations. Patients were divided according to systemic therapy: CT, ICI, or CT-ICI respectively. Primary endpoint was overall survival (OS), compared using Kaplan-Meier and Cox methodology. Secondary endpoint was intracranial progression free survival (icPFS). Results: Between 01-2018 and 05-2021, 118 newly diagnosed ns-NSCLC patients with BM were included (52 CT, 38 ICI and 28 CT-ICI). Median follow-up was 30.0 months [95% CI: 25.9-36.0]. Intracranial radiotherapy was delivered for 75.0%, 68.4% and 67.9% of patients for CT, ICI and CT-ICI groups (p = 0.805) respectively. OS rates at 24 months were respectively 25.3% (95% CI: 15.7-40.9), 44.6% (95% CI: 30.8-64.7) and 50.5% (95% CI: 34.3-74.4) in CT, ICI and CT-ICI groups (p = 0.048). Twelve-month icPFS was respectively 17.0% (95% CI: 9-32), 47% (95% CI: 33-66) and 45% (95% CI: 30-69) in CT, ICI and CT-ICI groups . After adjustment, ICI and CT-ICI were associated with a better OS compared to CT (HR = 0.46, 95%CI: 0.23-0.89, p = 0.021 and HR = 0.52, 95%CI: 0.27-1.01, p = 0.054 respectively). ICI and CT-ICI were associated with a significant reduction in the risk of intracranial progression by 54% (HR = 0.46, 95%CI: 0.25–0.84, p = 0.0123) and 59% (HR = 0.41, 95%CI: 0.23–0.77, p = 0.0050) compared to CT. Stereotactic radiosurgery was associated with an increased icPFS compared to systemic therapy alone (HR = 0.51, 95% CI: 0.29 – 0.92, p = 0.0247), whereas whole-brain was not (p = 0.096). Conclusions: Real-life ns-NSCLC patients with BM at diagnosis treated frontline with ICI presented OS and icPFS benefit compared to CT alone. A prospective assessment of the ideal type and sequence of systemic and local therapy should be conducted.