Patients with hepatitis C cirrhosis may sometimes have persistently elevated alpha feto protein (AFP) despite a lack of evidence for disease by ultrasound or computed tomography (CT). While this pattern may represent a benign manifestation of hepatitis C cirrhosis (HCC), it raises concern for the possibility of an occult hepatocellular carcinoma. It has previously been shown that positron emission tomography (PET scan) may detect occult cholangiocarcinoma in high-risk patients with primary sclerosing cholangitis. We hypothesized that PET scanning might similarly serve for occult HCC in hepatitis C cirrhotics. PET scanning was performed on eight hepatitis C cirrhotics who were on the liver transplantation list and displayed persistently elevated AFP (>100 ng/mL) but no detectable lesions on abdominal CT scan. The results of PET detection of occult HCC were compared to those obtained with lipiodol-enhanced CT scanning and with histologic examination of the live explant. Explant histology or prolonged clinical follow-up showed two subjects to have conclusive evidence of HCC; the remainder, no evidence of malignancy. Although PET imaging did not reveal abnormal lesions in any subject; lipiodol-enhanced CT scans revealed abnormal lipiodol retention in both subjects with HCC. These preliminary findings suggest that PET has no role in detecting occult HCC in high-risk patients. Additionally, these data suggest that some hepatitis C cirrhotics with persistently elevated AFP but no detectable lesions by conventional CT scan may show occult HCC using lipiodol-enhanced CT scans.