Background & Aims: Current management guidelines for hepatocellular carcinoma (HCC) do not require biopsy to prove the diagnosis. We evaluated our experience of patients with liver disease and hepatic lesions suspicious for HCC who underwent both fine-needle aspiration and core biopsy and correlated the results with those from commonly used noninvasive approaches. Methods: We retrospectively reviewed the outcomes of a series of patients undergoing biopsy because of a suspicion of HCC and compared sensitivity, specificity, and predictive value of biopsy with existing noninvasive methods for diagnosing HCC. Results: HCC was diagnosed by biopsy in 74 (63%) of 118 cases, and an additional 10 were found to have HCC on follow-up. Patients with positive biopsy results had significantly higher serum α-fetoprotein levels (median, 57 vs 12; P = .014) than those with negative biopsies, although these 2 groups were otherwise similar with regard to tests of liver function, lesion size on imaging, and Child-Pugh class. No patient developed evidence of tumor spread along the needle track after biopsy. We compared the diagnosis of HCC by biopsy with noninvasive diagnostic criteria advocated by the European Association for the Study of the Liver and those used by the United Network for Organ Sharing. Compared with criteria of the European Association for the Study of the Liver and the United Network for Organ Sharing, biopsy had greater sensitivity, specificity, and predictive value. Conclusions: We recommend a greater role for image-guided biopsy of lesions greater than 1 cm clinically suspicious for HCC to allow adequate treatment planning because the risks of biopsy appear small and the potential benefits significant. Obtaining material for both cytologic and histologic examination at biopsy maximizes the diagnostic yield.