Aim: The objective of our study was to assess the efficacy of immune checkpoint inhibitors (ICIs) on patients with non-small-cell lung cancer (NSCLC) harboring oncogenic alterations. Methods: We retrospectively enrolled patients with advanced non-squamous NSCLC who were treated with anti-PD-1-based monotherapy or combined immunotherapy. Major characteristics including PD-L1 expression, treatment, and survival were analyzed. Results: In total, 309 non-squamous NSCLC patients with a median age of 61 years (range 20-88 years) including 70.9% male were retrospectively enrolled. The molecular alterations involved epidermal growth factor receptor (EGFR) (n = 81), V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) (n = 31), anaplastic lymphoma kinase (ALK) (n = 1), human epidermal growth factor receptor 2 (HER2) (n = 12), V-raf murine sarcoma viral oncogene homolog (BRAF) (n = 2), rearranged during transfection (n = 4), and c-ros oncogene 1 (ROS1) (n = 3). In the EGFR subset, the ORR was 30.9% (n = 81) and PFS was significantly shorter than WT group (median PFS: 5.7 months vs. 7.1 months; P = 0.0061). In subgroup analyses, ICI combined therapy was significantly correlated with a longer PFS compared with ICI monotherapy (median PFS: 7.7 months vs. 4.7 months; P = 0.0112). In KRAS patients, ORR was 51.6% (n = 31). No significant difference was found in subgroup analyses. The ORR and PFS were 16.7% (n = 12) and 28.6% (n = 7), 7.8 months and 9.0 months for HER2 and EGFR Exon20 insertion patients, respectively. Three ROS1 patients were enrolled with a PFS of 16.0, 34.2, and 45.0 months individually, and one ALK patient with PFS of 4.4 months was identified. No response was found in two BRAF patients. Conclusion: ICI-based combination therapy can bring benefit to patients with EGFR-mutant NSCLC. ICI-based combination therapy could be considered for patients with ROS1 rearrangement, HER2 mutation and EGFR Exon20 insertion NSCLC.© The Author(s) 2022.