Serum autoantibodies have been reported to react with tumor‐associated antigen (TAA) in various cancers. This multicenter study evaluated the diagnostic and prognostic value of six autoantibodies against a panel of six hepatocellular carcinoma (HCC)‐associated antigens, including Sui1, p62, RalA, p53, NY‐ESO‐1 and c‐myc. A total of 160 patients with HCC and 74 healthy controls were prospectively enrolled from six institutions. Serum antibody titers were determined by enzyme‐linked immunosorbent assays. The sensitivities were 19% for Sui1, 18% for p62, 17% for RalA, 11% for p53, 10% for NY‐ESO‐1 and 9% for c‐myc. Overall sensitivity of the TAA panel (56%) was higher than that of α‐fetoprotein (41%, P < .05). The combined sensitivity of the TAA panel and α‐fetoprotein was significantly higher than that of α‐fetoprotein alone (P < .001). The difference in overall survival of TAA panel‐positive and panel‐negative patients was significant when the Stage I/II patients were combined (P = .023). Overall survival was worse in NY‐ESO‐1 antibody‐positive than in NY‐ESO‐1 antibody‐negative patients (P = .002). Multivariate analysis found that positivity for the TAA panel was independently associated with poor prognosis (P = .030). This TAA panel may have diagnostic and prognostic value in the patients with HCC.