BACKGROUND: Kirsten rat sarcoma homolog () mutations are one of the key drivers in non-small cell lung cancer (NSCLC) and FDA-approved specific inhibitors of -G12C mutation are available clinically. However, inhibitors of certain KRAS mutation subtypes remain unavailable, especially rare mutations including G13C, G13D, and Q61H. In this study, we retrospectively investigated the outcomes of NSCLC patients with rare -mutation to determine if they may benefit from immune checkpoint inhibitors (ICIs). METHODS: Our retrospective study involved 240 advanced NSCLC patients with mutations, who visited Shanghai Chest Hospital from July 2018 to July 2021. Complete clinical and pathological data were recorded and progression-free survival (PFS) and overall survival (OS) were adopted as primary endpoints. RESULTS: The median follow-up time was 36.5 months (range, 30.8-42.1 months) and the median OS was 9.7 months (range, 7.6-11.8 months). Of the 240 patients evaluated, 130 (54.2%) received chemotherapy and 110 (45.8%) received ICI-based treatment. Among the patients who received chemotherapy, patients with rare -mutations presented worse survival outcomes (median PFS, 3.4 4.1 months, P=0.047; median OS, 5.2 7.1 months, P=0.02) than conventional -mutant patients. PFS and OS of rare -mutation patients were prolonged after immunotherapy (median PFS 7.3 3.4 months, P<0.001; median OS, 13.3 5.2 months, P<0.001) and had no significant difference compared with conventional -mutant patients, in part of them whose programmed death-ligand 1 (PD-L1) expression data before immunotherapy were available (n=72), patients with a higher rate of PD-L1 positive tumor cells (≥50%) presented elevated PFS and OS. CONCLUSIONS: Despite having potential survival disadvantage compared with other NSCLC patients, rare KRAS-mutant patients (other than G12A, C, D, V) could benefit specifically from ICI-based therapy and survival outcomes are correlated with PD-L1 expression.