Objective: To investigate human epididymis protein 4 (HE4) levels in transitional cell carcinoma (TCC) of the urinary system and its relationship with clinicopathological features. Methods: 102 patients with TCC, 60 with benign urinary diseases, and 60 healthy controls were included in this study. The HE4 levels were used to analyze different clinicopathologic characteristics and changes between pre- and postsurgical operation. Results:. The HE4 level was significantly increased in patients with TCC compared to patients with benign urinary diseases patients (P<0.01) and healthy controls (P<0.01), and the level of HE4 in patients with superficial TCC (Tis Ta T1) was significantly higher than that of the benign urogenitall group (P<0.05) and healthy controls (P<0.05). There was a significant difference between HE4 levels in patients before and after operation (P<0.05). There was no difference between HE4 levels based on tumor recurrence, clinical TNM stage, lymph node metastasis, or pathological stage (P>0.05). The HE4 level was also different between patients with a single tumor versus patients with multiple tumors. The area under the curves of HE4 is 0.821. The sensitivity and specificity of HE4 at a cutoff value of 45.7 pM were 67.6 and 88.3%, respectively. Conclusions: HE4 may be a screening tool for early diagnosis of TCC in the urinary system, and may become a prognostic marker for TCC in the urinary system. J. Clin. Lab. Anal. 23:357-361, 2009. (C) 2009 Wiley-Liss, Inc.