Prognostic biomarkers that stratify patients with cancer are needed. Recent studies from Asia have implicated SALL4, a stem cell marker, as useful in identifying aggressive cases of hepatocellular carcinoma (HCC), and >50% of the cases tested had upregulation by microarray or dense immunoreactivity. Given the differences in predominant etiologic factors between the Asian and Western HCC, we sought to determine the prevalence of SALL4 immunoreactivity and its clinical relevance in Western HCC patients. We constructed tissue microarrays from 236 adult HCCs. Two cores each of tumor and nontumor tissue were included for each case. SALL4 immunohistochemistry was scored in a semiquantitative manner and the results correlated with recurrence-free and overall survival, in addition to standard demographics. Among the 236 cases, 165 (70.0%) were male. The median age was 59 years (range: 19 to 83 y). The majority (78.4%) of patients were white, followed by African American (15.7%), Asian (3.8%), Hispanic (1.7%), and Native American (0.4%). The majority of patients had hepatitis C (42.8%), followed by alcoholic liver disease and hepatitis B (both 8.9%), and nonalcoholic steatohepatitis (3.8%). SALL4 immunoreactivity was detected in a total of 3 cases (1.3%), and nonreactivity was validated on tissue sections from 73 cases. By univariate analysis, the SALL4-positive cases had significantly higher tumor grade (P=0.0251), more frequent lymphovascular invasion (P=0.0150), and shorter recurrence-free survival (7.90 vs. 57.54 mo; P=0.0115) and overall survival (7.90 vs. 64.87 mo; P=0.0018). Although SALL4 immunoreactivity in Western HCC is correlated with higher grade and poor prognosis, this is a rare event. Therefore, universal application of SALL4 as a biomarker for HCC should be performed with caution.