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Kidney renal clear cell carcinoma (KIRC) is a common malignant tumor in human genitourinary system. Previous studies have shown that the homeobox‐D (HOXD) cluster genes, which belong to the homeobox (HOX) family, are involved in the progression of multiple types of cancer. However, the expression profile and prognostic values of the HOXD genes in KIRC remain largely unknown. Herein, we comprehensively analyzed the transcriptional levels and prognosis of HOXD genes in KIRC using four online The Cancer Genome Atlas analysis databases (GEPIA, UALCAN, starBase v3.0, and LinkedOmics). We found that several members of the HOXD gene family were abnormally expressed in KIRC and correlated with patient prognosis. The messenger RNA levels of HOXD1, HOXD8, and HOXD10 were significantly downregulated in KIRC tissues as compared with the normal tissues. Low expression of HOXD1 or HOXD8 predicted poor overall survival (OS) of KIRC patients, and downregulated HOXD1, HOXD3, or HOXD4 indicated unfavorable patient disease‐free survival (DFS) in KIRC. Through integrated analysis, we found that HOXD1 was lowly expressed in KIRC and correlated with patient OS, DFS and advanced tumor stages. Moreover, gene set enrichment analysis showed that HOXD1 may be mainly implicated in cell cycle regulation, tumor growth factor‐β (TGF‐β) and Wnt signaling pathways in KIRC. Furthermore, both loss‐of‐function and gain‐of‐function experiments demonstrated that HOXD1 inhibited cell proliferation, cell cycle and the TGF‐β signaling in KIRC. Taken together, our findings suggest that HOXD1 is a novel potential tumor suppressor in KIRC. [ABSTRACT FROM AUTHOR]