Background: Detection of hepatocellular carcinoma (HCC) in high risk populations has traditionally involved the use of ultrasound (US), followed by computed tomography (CT) or magnetic resonance imaging (MRI) for confirmation of suspected lesions. The aim of our study was to determine, retrospecttively, in an unselected population of patients with cirrhosis, if an initial US could be as accurate as a subsequent CT or MRI in detecting HCC. Methods: 1600 consecutive cases from 2004-2007 in which US was performed for HCC screening were evaluated. 160 were identified which had an initial US followed by CT or MRI within 6 months. This group included 34 cases of HCC and 126 controls without HCC. Results: 26 cases of HCC were correctly identified by US, representing a sensitivity of 76.5%; the mean alpha-fetoprotein (AFP) level was 440.4 ng/dL. The other 8 cases had a false negative US; the mean AFP was 212.4 ng/dL. In 125 controls the mean AFP was 17.14 ng/dL. This group had only 12 patients, or 9.6%, with an AFP greater than 20 ng/dL, and only 1 who had an AFP greater than 400 ng/mL. In this study, the positive predictive value of US for detecting HCC was 96.3%, while the negative predictive value was 94.0%. Combining US with the AFP level, and using a cutoff of 20 ng/dL, the sensitivity was increased to 87.5%. In this series of 160 patients, only 2 patients with HCC had a negative US and normal serum AFP. Conclusion: In combination with regular monitoring of AFP levels, US can eliminate more expensive imaging studies until further investigation by CT or MRI of questionable US results or elevated AFP is necessary, thus reducing the overall cost of monitoring these populations.