BACKGROUND While protein kinase, DNA-activated, catalytic subunit (PRKDC) plays an important role in double-strand break repair to retain genomic stability, there is still no pan-cancer analysis based on large clinical information on the relationship between PRKDC and different tumors. For the first time, this research used numerous databases to perform a pan-cancer review for PRKDC to explore the possible mechanism of PRKDC in the etiology and outcomes in various tumors. METHODS PRKDC's expression profile and prognostic significance in pan-cancer were investigated based on various databases and online platforms, including TIMER2, GEPIA2, cBioPortal, CPTAC, and SangerBox. We applied the TIMER to identified the interlink of PRKDC and the immune infiltration in assorted tumors, and the SangerBox online platform was adopted to find out the relevance between PRKDC and immune checkpoint genes, tumor mutation burden, and microsatellite instability in tumors. GeneMANIA tool was employed to create a protein-protein interaction analysis, gene set enrichment analysis was conducted to performed gene enrichment analysis. RESULTS Overall, tumor tissue presented a higher degree of PRKDC expression than adjacent normal tissue. Meanwhile, patients with high PRKDC expression have a worse prognosis. PRKDC mutations were present in almost all The Cancer Genome Atlas tumors and might lead to a better survival prognosis. The PRKDC expression level was shown a positive correlation with tumor-infiltrating immune cells. PRKDC high expression cohorts were enriched in "cell cycle" "oocyte meiosis" and "RNA-degradation" signaling pathways. CONCLUSIONS This study revealed the potential value of PRKDC in tumor immunology and as a therapeutic target and prognostic biomarker in pan-cancer.