<p>Thyroid hormone receptor-interacting protein 13 (<i>TRIP13</i>) is involved in the regulation of mitosis and is overexpressed in multiple cancers. However, there is no systematic assessment of the role of TRIP13 in the immunotherapy response across human cancers. Therefore, a pan-cancer analysis involving expression, prognosis, immune-related mechanisms, and biomarker values was performed to explore the associations between <i>TRIP13</i> expression and the immunotherapy response. <i>TRIP13</i> is highly expressed in various types of cancer, increasing patient outcomes in eight types of cancer. <i>TRIP13</i> expression was correlated with significant tumor mutation burden and microsatellite instability, and its mutations were linked with poor prognosis in patients with adrenocortical carcinoma. <i>TRIP13</i> promoted endothelial cell and hematopoietic stem cell infiltration in human cancers. Additionally, <i>TRIP13</i> mutation significantly increased the infiltration of CD8 + T cells in kidney renal clear cell carcinoma, which might contribute to poor prognosis. Furthermore, three key genes that interact with <i>TRIP13</i> were identified: CDC20, RAD1, and MAD2L1, which are related to the cell cycle and ultimately promote tumorigenesis and proliferation. The expression of <i>TRIP13</i> was significantly greater in kidney renal clear cell carcinoma, liver hepatocellular carcinoma, and pancreatic adenocarcinoma cells than in corresponding normal cells according to qPCR. Taken together, these findings indicate that <i>TRIP13</i> is associated with poor prognosis in eight human cancers and serves as a novel biomarker for predicting immunotherapy efficacy. Our first pan-cancer study contributes to personalized precision medicine in cancer immunotherapy, promoting subsequent clinical management and improving patient prognosis.</p>