Angiopoietin-like protein 4 (ANGPTL4) has been reported to promote tumor growth, metastasis, and angiogenesis under certain conditions. The aim of this study was to examine ANGPTL4 expression in tumor and serum tissues from esophageal squamous cell carcinoma (ESCC) patients. A total of 78 ESCC patients treated with radical resection were enrolled in this study. Immunohistochemistry was used to detect ANGPTL4 expression in ESCC tissues. Serum ANGPTL4 levels were determined via enzyme-linked immunosorbent assay (ELISA). The receiver operating characteristics curve was constructed to describe diagnostic specificity and sensitivity. There were 52 cases (69.2 %) showing a higher level of ANGPTL4 expression in tumor tissues than that in normal tissues, and the rate of ANGPTL4 protein high/moderate expression in ESCC and normal tissues was 55.1 % (43/78) and 6.4 % (5/78), respectively, with a significant difference (P < 0.001). Moreover, the high/moderate of ANGPTL4 protein was significantly associated with lymph metastasis, clinical stage, and adverse 2-year progression-free survival. In addition, serum ANGPTL4 level in ESCC patients was much higher than that in patients with benign esophageal disease (P < 0.001), and area under the curve was 0.94 (95 % CI 0.886390–0.978173, P < 0.001). But serum ANGPTL4 level was significantly decreased at post-operative 7–10 days (P = 0.004). ANGPTL4 upregulation may play an important role in ESCC development, and serum ANGPTL4 level may be a potential tumor marker for ESCC diagnosis and prognosis.