Hepatocellular carcinoma (HCC) is a type of inflammation-related cancer that usually follows chronic inflammations. Leukotriene D4 (LTD4) is a potent biologically active arachidonic acid-derived lipid mediator that is intimately involved in inflammations and cancers. Although previous researches found overexpression of LTD4 in several other cancers, the circulating LTD4 level in HCC remains unknown. The aim of this study was to examine concentrations of LTD4 and analyze its roles in HCC. The results showed that remarkably high circulating LTD4 in HCC versus healthy subjects (p < 0.001). The levels of LTD4 were neither associated with parameters expressing tumor burden, such as AFP, nor with inflammation factors AST and γ-GT. In addition, the significant increase of circulating LTD4 levels was obtained in patients with HCC accompanied by chronic hepatitis B (CHB), compared with those patients suffering HCC alone(P < 0.05). Furthermore, although the slightly lower levels of LTD4 were detected in HCC patients with non-metastasis and therapy compared with metastasis and non-therapy, no significant differences were detected. Taken together, the levels of circulating LTD4 are elevated in HCC and it may participate in the pathogenesis of HCC as an inflammatory factor from CHB disease to HCC.