Abstract Background The effect of pain genes (NAV1, EHMT2, SP1, SLC6A4, COMT, OPRM1, OPRD1, CYP2D6, and CYP3A4) have not been reported previously in kidney renal clear cell carcinoma (KIRC) patients and thus we made a comprehensive analysis of pain genes in the prognosis of KIRC and tumor immunotherapy. Methods In this study, TCGA, Kaplan–Meier plotter, Metascape, STRING, Human Protein Atlas, Single Cell Expression Atlas database, LinkedOmics, cBioPortal, MethSurv, CancerSEA, COSMIC database and R package (ggplot2, version 3.3.3) were used for comprehensive analysis of pain genes in KIRC. Pearson and Spearman correlation coefficients were for co‐expression analysis. Immunotherapy and TISIDB database were used for tumor Immunotherapy. Results Representative pain genes (SP1, SLC6A4, COMT, OPRD1, CYP2D6, and CYP3A4) were statistically significant (p