Hepatocellular carcinoma (HCC) is a typical inflammation‐related malignancy characterized by high postoperative recurrence and metastasis. Although several inflammatory cells and inflammatory signatures have been linked to poor prognosis, the inflammation‐associated molecular mechanisms of HCC development and progression are largely unknown. Here we show that triggering receptor expressed in myeloid cells (TREM)‐1, a transmembrane receptor expressing in myeloid cells, was also expressed in tumor‐activated hepatic stellate cells (HSCs) and associated with the aggressive behavior of HCC cells. Enzyme‐linked immunosorbent assay was used to measure the expression levels of soluble TREM‐1 (sTREM‐1) in activated hepatic stellate cells supernatant and 92 preoperative and postoperative plasmas of patients with malignancy and/or benign liver tumor/disease, respectively. Expression levels of TREM‐1 were assessed by immunohistochemistry in tissue microarray from 240 patients with HCC. As a result, increased secretion of sTREM‐1 from activated HSCs was observed after co‐culture with HCC cell lines (P < 0.001), and conditioned medium collected from activated HSCs/cancer associated myofibroblasts (CAMFs) with or without agonist/inhibitor of TREM‐1 significantly changed the migratory ability of HCC cells. The levels of sTREM‐1 were significantly higher in patients with HCC than those with benign liver tumors (P < 0.005). Peritumoral density of TREM‐1 was shown to be an independent prognosis predictor according to univariate (P < 0.001 for both overall survival and time to recurrence) and multivariate analysis (P = 0.008 for overall survival; P = 0.005 for time to recurrence). Thus, these observations suggest that TREM‐1 is related to the aggressive tumor behavior and has potential value as a prognostic factor for HCC. (Cancer Sci 2012; 103: 984–992)