Background: Tumor mutation burden (TMB) may predict the immune checkpoint inhibitor (ICI) response. The TMB calculation includes all nonsynonymous somatic mutations, but not all mutations are favorable, and the efficiency of TMB is attenuated by including adverse mutations. Moreover, no universal cutoff value of a high TMB hinders its application in practice. Methods: Tumor mutation score (TMS), defined as the number of genes with nonsynonymous somatic mutations, TMS55, defined as the TMS of 55 favorable prognostic genes, and TMB were calculated and compared in 1,661 advanced cancer patients treated with ICIs and 3,840 matched advanced cancer patients not treated with ICIs among ten cancer types. Results: TMS55 was significantly associated with TMB. In 1,661 ICI-treated patients, 55 genes were significantly associated with prolonged overall survival (OS), and a high TMS55 (TMS55 >5) was associated with a smaller hazard ratio (HR) and P value than a high TMB (highest 20% in each histology group) in predicting OS. The C-index of TMS55 was significantly higher than that of TMB (TMS55 0.65 vs. TMB 0.54, P<0.001). Moreover, TMS55 was significantly associated with improved survival in more tumor types than TMB, especially in non-small cell lung cancer (NSCLC), melanoma, bladder cancer and colorectal cancer. In 3,840 non-ICI-treated patients, a high TMS55 and TMB predicted poor OS. Conclusions: The novel TMS55 might be better than TMB as a biomarker for patients treated with ICIs. The easy calculation and universal cutoff value of TMS55 will not be affected across platforms and is feasible in clinical settings, which may greatly promote its application in the clinic with further validation.