BACKGROUND.Postoperative interferon‐α (IFN‐α) therapy improved survival in patients with hepatitis B virus (HBV)‐related hepatocellular carcinoma (HCC). The identification of predictive markers of outcome will help to select patients who are most likely to benefit from treatment.METHODS.An immunohistochemical study of P48 was performed on specimens that were collected from patients in a randomized trial who received postoperative IFN‐α therapy (Group 1; n = 80 patients) and who did not receive postoperative IFN‐α therapy (Group 2; n = 75 patients). Positive P48 expression was graded as ≥20% positive cells in 1 sample.RESULTS.Eighty‐one patients were positive for P48, and 74 patients were negative for P48. The clinicopathologic data were comparable between patients with P48‐negative and P48‐positive staining. Disease‐free survival (DFS) and overall survival (OS) in P48‐positive patients were better than that in P48‐negative patients in Group 1 (DFS, P = .036; OS, P = .014), however, DFS and OS did not differ between patients with positive and negative P48 in Group 2. OS in P48‐positive patients from Group 1 was better than that in patients with P48‐positive patients from Group 2 (OS, P = .001) but did not differ when P48 was negative. In Group 1, the risk factors for DFS were cirrhosis and P48 staining, and the risk factors for OS were tumor differentiation and P48 staining. Receiver operating curve analysis indicated that, in the first 2 years of DFS, combined cirrhosis and P48 had good predictive accuracy; and, in the first 4 years of OS, combined tumor differentiation and P48 had good predictive accuracy.CONCLUSIONS.P48 was useful as a predictive marker of outcome after postoperative IFN‐α treatment in patients with HBV‐related HCC. Cancer 2006. © 2006 American Cancer Society.