Objectives <p>KRTCAP2 plays an important function in glycoprotein synthesis. However, the role of KRTCAP2 in kidney renal clear cell carcinoma (KIRC) remains unknown. Therefore, this study aimed to analyze the role of KRTCAP2 in KIRC through comprehensive bioinformatic analysis.</p> Methods <p>All raw data were downloaded from the Cancer Genome Atlas (TCGA) and further validated in our own datasets. KRTCAP2 mRNA expression and methylation data in KIRC were examined using the tumor immune estimation resource (TIMER) and the University of Alabama at Birmingham Cancer Data Analysis Portal (UALCAN) database resources. The expression of KRTCAP2 in paraffin-embedded tissues (100 cancer samples and 100 paracancerous tissues) from our cohort was examined by immunohistochemical assay. The Linkedomics database was used to study signaling pathways associated with KRTCAP2. TIMER and TISIDB were used to analyze the correlation among KRTCAP2, KRTCAP2 co-expressed genes, tumor-infiltrating immune cells, and immunomodulators.</p> Results <p>The mRNA expression of KRTCAP2 in KIRC was higher than that in adjacent normal tissues. It was confirmed by immunohistochemistry that the expression of KRTCAP2 in tumor tissues was higher than that in adjacent tissues at the protein level. Combining the above analyses, we found that the high expression of KRTCAP2 is closely related to the poor prognosis of KIRC patients. Furthermore, multivariate Cox regression analysis indicated that KRTCAP2 was an independent prognostic factor for KIRC. GO and KEGG pathway analysis showed that KRTCAP2 co-expressed genes were mainly associated with various immune-related pathways, mitochondrial protein complex formation, the tricarboxylic acid cycle, and cellular aerobic respiration pathways. Through the database, we found that the expression of KRTCAP2 in KIRC was positively correlated with NK CD56 bright cells, cytotoxic cells, CD8 T cells, Treg cells, and pDC cells. The expression of KRTCAP2 was negatively correlated with Tcm cells, mast cells, iDCs, macrophages, eosinophils, neutrophils, and Tgd cells. We used our own 40 KIRC cancer tissues and paracancerous tissues to perform immunohistochemical evaluation of CD4, CD5, CD68, CD163, CD2, CD7, PD-L1, HER-2, and their correlation with KRTCAP2 expression levels. The results showed that among 40 KIRC patients, the positive expression rate of CD4 was 37.5% (15/40), the positive expression rate of CD5 was 40% (16/40), the positive expression rate of CD68 was 55% (22/40), and the positive expression rate of CD163 was 55% (22/40). The positive expression rate was 47.5% (19/40), the positive expression rate of CD2 was 35% (14/40), the positive expression rate of CD7 was 32.5% (13/40), the positive expression rate of PD-L1 was 42.5% (17/40), and the positive expression rate of HER-2 was 5% (2/40). In addition, it was found that the expression level of KRTCAP2 was positively correlated with CD5, CD68, CD68, CD2, CD7, and CD163. Our data also found that the expression of KRTCAP2 was positively correlated with the expression of the chemokines and receptors CCL4, CCL5, XCL2, XCL1, CCR10, and CXCR3, and negatively correlated with the expression of CCR4 and XCR1. Interestingly, KRTCAP2 expression levels were positively correlated with the expression of immunostimulatory and immunosuppressive CD27, CD40, CD48, CD70, LAG3, LGALS9, PDCD1, and PVRL2 in KIRC.</p> Conclusion <p>KRTCAP2 may have an important regulatory role in ATPase activity and can be used as a prognostic biomarker for determining prognosis and immune infiltration in KIRC.</p>