Cereblon (CRBN) has emerged as a vital E3 ubiquitin ligase for Proteolysis-targeting chimera (PROTAC) design. However, few studies focus on the physiological mechanism of CRBN, and more studies are needed to explore the influence of CRBN on tumorigenesis. This pan-cancer analysis aims to explore the prognostic and immunologic roles of CRBN, and provide new insight for CRBN into cancer treatment and PROTAC design.The TCGA database, TIMER 2.0 database, and TISIDB database were used to analyze the role of CRBN in pan-cancer. Multiple bioinformatic methods (ssGSEA, Kaplan-Meier, univariate cox regression, ESTIMATE, CIBERSORT) were applied to investigate the CRBN expression status, gene activity, prognostic values, and its correlation with immune scores, immune infiltration, immune-related functions, HALLMARKs functions, and response to immunotherapy in pan-cancer.In most cancer types, the expression and activity of CRBN in tumor groups were lower compared with normal groups. Upregulated CRBN expression may indicate a better prognosis for cancer patients. The Immune score, stromal score, and tumor purity varied greatly among different cancer types. GSEA analysis showed that high CRBN expression was correlated with the downregulation of tumor-promoting signaling pathways. The level of CRBN was associated with Tumor mutation burden (TMB), Microsatellite instability (MSI), objective response rate (ORR), and immune cell infiltration in a few cancer types.Pan-cancer analysis reveals the potential role of CRBN as a prognostic biomarker and versatile immunologic roles in different cancer types. Upregulated expression of CRBN may be beneficial to CRBN-related immunotherapy and PROTAC design.© 2023 The Authors.