An 86-year-old male patient with sustained virological response of chronic hepatitis type C was diagnosed with hepatocellular carcinoma (HCC) in hepatic segment 3. He was treated with transcatheter arterial chemoembolization (TACE) and radiation therapy because the tumor was located at the edge of the liver and umbilical portion of the portal vein. The value of alpha-fetoprotein (AFP) which is a serological tumor marker decreased, and the tumor size did not increase;however, another tumor was recognized at S3 of the liver 15 months post-TACE. The patient underwent a second TACE, and computed tomography revealed HCC recurrence at S3, S8/4, and S1 of the liver 6 months later. The patient refused to undergo another treatment, but the AFP and Des-γ-carboxy prothrombin values and the tumor size decreased 3 months postrecurrence. Two months after multiple recurrences of HCC, he received the third dose of messenger RNA-based vaccine for severe acute respiratory syndrome coronavirus 2. Tumor regression may occur after an immune-inflammatory response induced by messenger RNA-based vaccine.