Background In our previous studies, we found the expression of 14-kD phosphohistidine phosphatase (PHPT1) was associated with lung cancer cells migration and invasion, and PHPT1 mRNA expression level in lung cancer tissues clinically correlated with lymph node metastasis In the present study, we aimed to further investigate the expression of PHPT1 protein in lung cancer Methods Expression of PHPT1 protein in tissue samples from 146 lung cancers and 30 normal tissues adjacent to lung cancers was assessed using immunohistochemical method Fisher's exact test was used to analyze expression patterns of PHPT1 protein in these tissue types Meanwhile, we studied the correlation between expression of PHPT1 protein and clinicopathological features in lung cancer Results Significantly higher expression levels of PHPT1 protein were found in lung cancer samples ( 53 42%) than in normal tissues adjacent to lung cancer (23 33%) (P=0 003) Fisher's exact test showed that lung cancer stage positively correlated with expression of PHPT1 protein (P=0 02), and lung cancer samples with lymph node metastasis showed higher PHPT1 protein expression (P=0 016) than the samples without lymph node metastasis Conclusions The results of this study agree with findings from our previous study of PHPT1 mRNA expression in lung cancer tissues, and strongly suggest that PHPT1 protein is closely associated with the carcinogenesis and metastasis of lung cancer Thus, therapy targeting PHPT1 (inhibition or silencing) could be potentially benefited for lung cancer patients Chin Med J 2010,123(22) 3247-3251