Hepatocellular carcinoma (HCC) is the third most common cause of cancer mortality among men worldwide. Serotonin is a biogenic amine, which may be involved in the tumorigenesis of HCC.We aimed to determine whether serotonin is a dependable marker for the diagnosis of HCC in cirrhotic patients in comparison with α-fetoprotein protein (AFP) and prothrombin induced by vitamin K absence-II (PIVKA-II).Serum serotonin, AFP, and PIVKA-II were measured in 262 patients with chronic hepatitis C (CHC): 82 cirrhotic patients with HCC (group I), 80 cirrhotic patients without HCC (group II), and 100 CHC-infected patients without cirrhosis (group III); in addition, 60 healthy controls were studied (group IV).AFP showed significant statistical differences among the groups studied (P0.001). PIVKA-II and serotonin levels showed no statistically significant differences between the patients with CHC group and the healthy controls (P1=0.614 and P1=0.13, respectively), whereas their levels were statistically higher in cirrhotic patients than patients with CHC (all P values0.001) and in the cirrhotic patients with HCC group than the cirrhotic patients without HCC (P0.001). A significant positive correlation was found between serum serotonin and AFP (rho=0.794; P0.001) and serum serotonin and PIVKA-II (rho=0.889; P0.001) among the patient groups. The receiver operator characteristic curve showed a higher area under the curve for serotonin than AFP and PIVKA-II (0.942, 0.824, and 0.921, respectively).Serotonin may be used together with PIVKA-II to screen for HCC in cirrhotic patients with CHC.