BackgroundCentrosomal protein 55 (CEP55) plays a significant role in specific cancers. However, comprehensive research onCEP55is lacking in pan-cancer.MethodsIn-house and multi-center samples (n= 15,823) were used to analyzeCEP55in 33 cancers. The variance ofCEP55expression levels among tumor and control groups was evaluated by the Wilcoxon rank-sum test and standardized mean difference (SMD). The clinical value ofCEP55in cancers was assessed using receiver operating characteristic (ROC) curves, Cox regression analysis, and Kaplan-Meier curves. The correlations betweenCEP55expression and the immune microenvironment were explored using Spearman’s correlation coefficient.ResultsThe data of clustered regularly interspaced short palindromic repeats confirmed thatCEP55was essential for the survival of cancer cells in multiple cancer types. ElevatedCEP55mRNA expression was observed in 20 cancers, including glioblastoma multiforme (p< 0.05).CEP55mRNA expression made it feasible to distinguish 21 cancer types between cancer specimens and their control samples (AUC = 0.97), indicating the potential ofCEP55for predicting cancer status. Overexpression ofCEP55was correlated with the prognosis of cancer individuals for 18 cancer types, exhibiting its prognostic value.CEP55expression was relevant to tumor mutation burden, microsatellite instability, neoantigen counts, and the immune microenvironment in various cancers (p< 0.05). The expression level and clinical relevance ofCEP55in cancers were verified in lung squamous cell carcinoma using in-house and multi-center samples (SMD = 4.07; AUC > 0.95;p< 0.05).ConclusionCEP55may be an immune-related predictive and prognostic marker for multiple cancers, including lung squamous cell carcinoma.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12890-023-02452-1.