Clear cell renal cell carcinoma (ccRCC) is a common type of kidney cancer and accounts for 2-3% of all cancer cases. Furthermore, a growing number of immunotherapy approaches are being used in antitumor treatment. Signaling lymphocyte activation molecule family (SLAMF) members have been well studied in several cancers, whereas their roles in ccRCC have not been investigated. The present study comprehensively assessed the molecular mechanisms of SLAMF members in ccRCC, performed using The Cancer Genome Atlas database, with analysis of gene transcription, prognosis, biological function, clinical features, tumor-associated immune cells and the correlation with programmed cell death protein 1/programmed death-ligand 1 immune checkpoints. Simultaneously, the Tumor Immune Dysfunction and Exclusion algorithm was used to predict the efficacy of immune checkpoint blockade (ICB) therapy in patients with high and low SLAMF expression levels. The results demonstrated that all SLAMF members were highly expressed in ccRCC, and patients with high expression levels of SLAMF1, 4, 7 and 8 had a worse prognosis that those with low expression. SLAMF members were not only highly associated with immune activation but also with immunosuppressive agents. The level of immune cell infiltration was associated with the prognosis of patients with ccRCC with high SLAMF expression. Moreover, high ICB response rates were observed in patients with high expression levels of SMALF1 and 4. In summary, SLAMF members may serve as future potential biomarkers for predicting the prognosis of ccRCC and emerge as a novel immunotherapy target.