Background/Aims. Hepatocyte Growth factor (HGF) is widely expressed growth factor that plays crucial role in invasion and metastasis of tumor cells through interaction with c-met receptor, which is frequently expressed in pancreatic cancer. However, the significance of HGF as a tumor marker to diagnose peri-ampullary cancer (PAC) is not clear at present. The purpose of this study is to: 1- determine the sensitivity, and specificity of plasma HGF in patients with PAC. 2- study the dynamic changes of HGF following pancreaticoduodenectomy (PD), which has not been described before. 3- Analyze the relationship between the preoperative and postoperative levels, and various clinical and histopathological parameters to determine the prognostic value of HGF. Methods: Plasma level of HGF was measured using ELISA kit in patients with PAC (n=57), benign periampullary tumors (BPT) (n=21), chronic pancreatitis (CP) (n=20), and in 20 healthy individuals who served as normal control (NC). The plasma samples were assayed in duplicate using 3 different dilutions. Following PD, plasma HGF level was further measured at 1, 6, 12, 24, and 48 weeks. A retrospective cohort study was conducted to analyze the relationships between HGF profiles and different clinical and histological parameters. Results: Patients with PAC had significantly higher plasma level of HGF compared to NC, patients with BPT, and CP (1574± 625 pg/ml; 670±185 pg/ml; 781±257 pg/ml; 881±303 pg/ml; P= 0.0001). At a cutoff value of 1120 pg/ml, 48/57 (84.2%) patients with PAC, none of the NC and BPT individuals, and only 4/20 (20%) patients with CP were positive. Receiver operating characteristics analyses for discrimination of PAC from BPT and CP provided an area under the curve of 0.919± 0.03 (95% CI, 0.82-0.97, P=0.0001) with a sensitivity of 84% and specificity of 89%. Following curative PD, HGF levels were higher at 1, and 6 weeks compared to the preoperative value. The level returned to baseline between 6-12 weeks, and normalized after 12 weeks. However, the levels did not return to normal in patients who experienced early recurrence. There were no correlation between the baseline level of HGF and the clinical and histological findings. Conclusion: The high sensitivity and specificity of plasma HGF in patients with PCA, suggest that HGF may be useful in the diagnosis of PAC. Furthermore, we have shown indirectly that HGF may not be secreted by the malignant cells per se. The higher immediate postoperative value compared to the baseline level reflected the stress of surgical resection. However, the sustained high level of plasma HGF following PD may be a factor related to early recurrence and metastasis.