Spontaneous regression of hepatocellular carcinoma (HCC) is associated with alcohol abstinence, herbal medication, radiation, ischemia and immune reaction against systemic or local infections. Herein, we report a case of 67-year-old man with spontaneous disappearance of HCC after local infection as a rare cause. The patient had no clinical symptoms except for markedly increased tumor marker of HCC (protein induced by vitamin K absence or antagonist-II: 731 mAU/mL). On computed tomography (CT) and magnetic resonance imaging, massive infiltrating HCC with portal vein invasion was confirmed. During conservative treatment, he was admitted due to suppurative diabetic foot. After medical treatment, HCC disappeared on follow-up CT scans, along with change in hepatic contour. The disappearance of HCC might be a result of immune response by treatment of the diabetic foot and that of ischemia by portal vein tumor thrombosis secondarily. We summarized case reports regarding spontaneous regression of HCC by infection and ischemia.