The tumor stroma is a source of many potential new tumor biomarkers, in which the immune response is of major importance. Little is known regarding how changes in stromal gene expression affect hepatocellular carcinoma (HCC) progression. We analyzed the expression of 28 stroma-related genes using quantitative RT-PCR in 122 HCC samples, and related the results to patient prognosis. Hierarchical clustering based on expression of the 28 genes, or the 6-Th1 cell markers, can classify HCC patients into prognostically different subgroups. We further identified a five-gene classifier (protective genes IRF1 and GZMB and risk genes CRTH2, VEGF, and MMP7) as a significant independent prognosticator for recurrence (hazard ratio [HR], 4.80; 95% confidence interval [CI], 2.31–9.96; P = 2.6 × 10−5) by multivariate analyses. Importantly, the classifier was further validated in an independent set of 172 HCC samples (HR, 2.21; 95% CI, 1.20–3.00; P = 0.002). The predictive ability of the classifier, as measured by area under the curve (0.713 and 0.613 for original and validation cohorts, respectively), was comparable to those of vascular invasion, Barcelona Clinic Liver Cancer stage, and TNM stage. The densities of various tumor stromal cells were analyzed by immunostaining. Comparing the immunostaining and gene expression data showed significant association of the gene classifier with the amount of reactive stroma in both cohorts. Thus, the signature reveals the strong prognostic capacity of immune responses, angiogenic activity, and ECM remodeling, highlighting the importance of stromal biology in HCC progression. Contained in this novel predictor may be targets suitable for new therapeutic interventions, or for use as independent prognosticators. (Cancer Sci 2011; 102: 1522–1531)