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Introduction: The nuclear export protein exportin 1（XPO1） regulates the export of a range of cargoes from the nucleus to the cytoplasm, and plays an important role in the maintenance of cellular homeostasis. Previous studies indicated that non-small-cell lung cancer（NSCLC） patients with XPO1 mutations were associated with poorer survival. However, up to now, the approaches for XPO1-inhibitors are still challenging, and the definite efficacy for XPO1 blockade is still undetermined in several cancer types including NSCLC. Therefore, finding novel strategies is urgently needed to improve the survival for XPO1-mutant NSCLC patients. Interestingly, NSCLC patients with XPO1 mutations were more likely to have high tumor mutational burden（TMB）, which suggested that immune checkpoint inhibitors（ICIs） could serve as an option for these patients. Nonetheless, as far as we known, there is no study investigate the efficacy of ICIs in NSCLC patients with XPO1 mutations.Methods: We integrated the MSK-TMB, POPLAR and OAK cohorts to evaluate the association between XPO1 mutation and the survival of NSCLC patients. A total of 350 ICI-treated NSCLC patients from the MSK-TMB cohort and 429 atezolizumab-treated NSCLC patients with available genomic sequencing data（biomarker evaluable population） from the POPLAR and OAK cohorts were included in this study. Importantly, XPO1 mutations were defined as any nonsynonymous or fusion mutations.Results: The incidence of XPO1 mutations was 1.2 %（9 of 779） in the entire cohort. Detailly, most of patients were non-squamous（6 of 9, 66.7 %）, were male（7 of 9, 77.8 %）, had missense mutation type for XPO1 gene（7 of 9, 77.8 %） and exhibited high TMB scores（above 10 mutations/Mb）（7 of 9,77.8 %）. At first, we analyzed the overall survival（OS） in NSCLC patients with XPO1 mutations and their wild type counterparts. Unfortunately, we found patients harboring XPO1 mutations had comparable OS compared with those without the mutation（median OS, 19 months versus 12 months,P = 0.186）. Considering the inferior impact of STK11/KEAP1 mutations on the efficacy of ICIs,which was already disclosed both in our cohorts and other studies, we further divided patients into pure XPO1-mutant, wild type and XPO1-STK11/KEAP1 mutant groups. Surprisingly, NSCLC patients with pure XPO1 mutations had significantly longer OS than wild type and XPO1-STK11/KEAP1 mutant cohorts（median OS, not reached versus 12 months versus 4 months, P =0.039）.Conclusions: Collectively, for the first time, we investigated the role of XPO1 mutations in NSCLC patients with ICIs treatment. Our results suggested that there was no significant difference in the efficacy of ICIs therapy between NSCLC patients with and without XPO1 mutations. However,considering the comutation status of STK11/KEAP1, we demonstrated that patients with pure XPO1 mutations were correlated with longer survival and could serve as a favorable prognostic biomarker in NSCLC. Nevertheless, the small sample of XPO1-m