Background. To analyze the clinical significance of serum p53 protein and anti-p53 antibodies as serological markers for hepatocellular carcinoma (HCC). Methods. We studied clinical data, i.e., age, sex, etiology, serum alpha-fetoprotein (AFP) level, TMN staging, and Okuda staging in 141 patients with HCC. The sera of these patients were analyzed for serum p53 protein and serum anti-p53 antibodies by enzyme-linked immunosorbent assay (ELISA). Results. Serum p53 antigen and serum anti-p53 antibodies were detected in the sera of 32 of the 141 (22.7%) patients and 26 of the 141 patients (18.4%), respectively. Of note, the HCC patients who were positive for p53 antigen (32/141) had no circulating anti-p53 antibodies. When both these groups of patients were combined as a serum p53 status-positive group, the total number in this group was 58 (41.1%). Positive status of p53 was not associated with age (P = 0.206), serum alpha-fetoprotein level (P = 0.851), Okuda staging (P = 0.243), or survival (P = 0.078), but was correlated significantly with TMN staging (P = 0.049). Interestingly, a shorter survival time (mean, 3.9 months) was noted in the serum p53 status-positive group, in comparison with the longer survival time (mean, 6.5 months) in the serum p53 status-negative group. Conclusions. Combination of the detection of serum p53 antigen and antibodies by ELISA may represent a suitable noninvasive investigation in assessing the clinical implications and prognoses of patients with HCC.