<h3>Purpose/Objective(s)</h3> MET-inhibitors have shown promising anti-tumor activity in patients with MET exon 14 mutant cancers. However, therapeutic strategies for MET non-exon-14 (MET-non-ex14) mutant cancer are still largely unknown. We evaluated the relationship between MET-non-ex14 mutations and the efficacy of immune checkpoint inhibitors (ICIs) in patients with multiple cancer types. <h3>Materials/Methods</h3> The clinical and genomic data of 1690 ICIs-treated cancer patients were obtained from the cBioPortal database (https://www.cbioportal.org). MET mutations were defined as any nonsynonymous mutations including missense, frameshift, nonsense and splice site mutations. We divided MET mutations into METex14 and MET-non-ex14 mutation subsets according to the mutated-position in MET exons. Kruskal-Wallis test was used to analyze the difference of tumor mutational burden (TMB) score, and χ2 test was applied for categorical variables. Log-rank test was used to analyze the differences between Kaplan-Meier survival curves. <i>P</i> values were 2-sided, and <i>P</i> < 0.05 was considered statistically significant. <h3>Results</h3> 1690 ICIs-treated patients with various cancer types were enrolled in this study, including non-small-cell lung cancer (NSCLC) (22.8%, 385/1690), melanoma (18.9%, 320/1690), bladder cancer (12.7%, 215/1690), and so on. A total of 51 patients (3.0%) harbored MET-non-ex14 mutations in the entire cohort, including one melanoma and one NSCLC patients with METex14 commutations. No significant differences in age, sex and cancer types were observed between patients with and without MET-non-ex14 mutations (<i>P</i> > 0.05). However, the TMB in patients with MET-non-ex14 mutations was significantly higher than those without these mutations (<i>P</i> < 0.001). Across 1661 patients with available overall survival (OS) data, MET-non-ex14 mutant patients had a significantly longer OS versus MET ex14-mutant/wild-type patients (median OS, not reached vs 18 months; <i>P</i> = 0.001). In NSCLC subgroup, 17 patients (4.4%) had MET mutations including six with MET-non-ex14 mutations, 10 with METex14 mutations and one with MET-non-ex14/METex14 commutations. MET-non-ex14-mutant patients (7/385, 1.8%) possessed a significantly higher TMB than METex14-mutant (10/385, 2.6%) and MET wild-type (368/385, 95.6%) populations, respectively (<i>P</i> = 0.008; <i>P</i> = 0.01, respectively). In the total of 356 NSCLC patients with available OS data, the OS was significantly longer in MET-non-ex14-mutant subgroup compared with their wild-type counterparts (median OS, not reached vs 11 months; <i>P</i> = 0.039). Additionally, patients with MET-non-ex14 mutations exhibited relatively better survival versus METex14-mutant patients (median OS, not reached vs 18 months; <i>P</i> = 0.175). <h3>Conclusion</h3> Our results indicated that MET-non-ex14 mutations were associated with higher TMB, and could be considered as a positive prognostic biomarker for immunotherapy in different cancer types.