ARTICLE ABSTRACTPurpose: To investigate the expression of myeloid differentiation factor 88 (MyD88) in hepatocellular carcinoma (HCC) and its prognostic value in patients with HCC.Experimental Design: Expression of MyD88 was detected by immunohistochemistry in surgical HCC specimens (n = 110). The correlation of MyD88 expression to clinicopathologic characteristics was analyzed. The involvement of MyD88 in tumor growth and invasion was investigated.Results: The expression of MyD88 was significantly higher in HCC tumors than that in adjacent nontumor tissues. Particularly, high expression of MyD88 was found in HCCs with late tumor stage (P = 0.029). Patients with high MyD88 staining revealed a higher recurrence rate (65% vs. 40%; P = 0.008). Kaplan–Meier analysis showed that recurrence-free survival (RFS; P = 0.011) and overall survival (OS; P = 0.022) were significantly worse among patients with high MyD88 staining. Univariate and multivariate analyses revealed that MyD88 was an independent predictor for OS and RFS. Ectopic expression of MyD88 promoted HCC cell proliferation and invasion in vitro. Suppression of MyD88 expression with lentivirus encoding short hairpin RNA reduced tumor growth and invasion, as well as lung metastasis. Finally, silencing of MyD88 inhibited the activation of NF-κB and AKT in HCC cells, whereas forced expression of MyD88 was able to enhance the activation of NF-κB and p38/extracellular signal–regulated kinase without Toll-like receptor/interleukin-1 receptor (TLR/IL-1R) signaling.Conclusion: Elevated expression of MyD88 may promote tumor growth and metastasis via both TLR/IL-1R–dependent and –independent signaling and may serve as a biomarker for prognosis of patients with HCC. Clin Cancer Res; 19(11); 2905–16. ©2013 AACR.