Objective To explore expression and clinical relevance of phosphohistidine phosphatase 1 (PHPT1) in clear-cell renal cell carcinoma. Methods Patients with clear-cell renal cell carcinoma who underwent radical or nephron-sparing nephrectomy were enrolled. Correlations between PHPT1 expression and demographic and clinical characteristics were analysed prospectively. Results In total, 122 patients (78 male/44 female) were included. In normal kidney tissue, PHPT1 expression was observed only in the proximal tubule. High PHPT1 expression levels were associated with larger tumour size, higher Fuhrman nuclear grade and advanced pathological tumour-node-metastasis (pTNM) stage compared with low PHPT1 expression levels. Patients with low PHPT1 expression showed better overall survival and progression-free survival compared with those with high PHPT1 expression. In addition, multivariate analysis showed that nuclear grade and pTNM stage were independent predictors of progression-free survival and overall survival in patients with clear-cell renal cell carcinoma. PHPT1 expression was also an independent predictor of overall survival but not progression-free survival. ConclusionsPHPT1 was expressed in the epithelium of proximal tubuli and nuclei of clear-cell renal cell carcinoma tissue samples. High levels of 14 kDa phosphohistidine phosphatase protein were negatively associated with overall survival and progression-free survival in patients with clear-cell renal cell carcinoma.