Abstract Purpose For the first-line treatment of KRAS mutant non-small cell lung cancer (NSCLC) patients, immunotherapy or platinum-based chemotherapy are the main treatment method. Here, we investigated the clinical efficacy and prognosis those two regimens as first-line treatment in real-world practice. Methods KRAS mutant NSCLC patients received chemotherapy or immunotherapy as first-line treatment from September 2014 to March 2022 were enrolled. Clinical characteristics, treatment scheme, clinical curative effect and follow-up data of enrolled patients were collected for analysis. Results Fifty patients received immunotherapy and 115 patients received chemotherapy were enrolled. Patients who received immunotherapy (HR = 0.350, 95%CI 0.156–0.781, P = 0.010), or pemetrexed-based regimen (HR = 0.486, 95%CI 0.255–0.928, P = 0.029), or antiangiogenic therapy (HR = 0.355, 95%CI 0.159–0.790, P = 0.011) were at a low risk of disease progression. And patients received antiangiogenic therapy had lower risk of death than those not (HR = 0.333, 95%CI 0.120–0.926, P = 0.035). Subgroup analysis revealed the immunotherapy compared to chemotherapy alone had lower risk of disease progression (HR = 0.377, 95%CI 0.166–0.856, P = 0.020) in PD-L1 expression ≥1% subgroup. And in non-G12C KRAS subgroup, but not in G12C KRAS subgroup, patients who received antiangiogenic therapy had lower risk of disease progression (HR = 0.254, 95%CI 0.098–0.656, P = 0.005) and death than those not (HR = 0.197, 95%CI 0.056–0.692, P = 0.011). In terms of different chemotherapy regimen, platinum-paclitaxel combined with antiangiogenic therapy achieved the highest ORR and DCR (P
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