Hepatocellular carcinoma (HCC) is the most frequent form of primary liver cancer and the fifth most prevalent cancer worldwide [1]. Spontaneous tumor regression was first defined by Cole and Everson [2] as complete or partial clearance of malignant cells in the absence of any specific treatment, particularly antineoplastic chemotherapy. However, it may also occur during or after therapy, a situation in which therapy could be endorsed with an undeserved antitumor effect. Spontaneous tumor regression was at first thought to be an extremely infrequent phenomenon, with an estimated incidence of 1 in 60,000–100,000 cases [3]. Its mechanism is largely unknown, however, it has important implications in clinical research and clinical practice. The number of cases of spontaneous regression reported in the literature is higher in HCC than in other neoplasms [4], possibly reflecting a higher incidence. However, due to its exceedingly low frequency it would probably not affect the results of any study on HCC therapy. Following our observation of two cases of spontaneous regression and one case of sustained, complete regression in the course of a chemotherapeutic regimen with marginal efficacy in the treatment of this tumor, we have searched the cases published in the English literature and reviewed the possible mechanisms involved in such remarkable events. We have retrospectively reviewed all the cases recorded in our liver unit in which an objective tumor remission was observed that could not be convincingly ascribed to a therapeutic effect of any rational intervention. These consist of tumor ablation, any sort of embolizing procedure performed in the hepatic artery or its branches (including intra-arterial injection of Lipiodol for diagnostic or staging purposes), or pharmacological therapy that might have a known antiproliferative effect. Medical records of these patients were thoroughly reviewed trying to find any possible event that may have triggered the observed remission.