To assess the efficacy of ultrasound-guided percutaneous acetic acid (15%, 20%, 30%, 40%, and 50% in concentration) injection for a large nodular hepatocellular carcinoma (HCC), percutaneous acetic acid injection was performed using 15% to 50% acetic acid in 28 patients who had one single nodular HCC larger than 3 cm or one main tumor with fewer than two HCCs smaller than 3 cm during the past 7.5 years; the main tumor was slightly hypervascular in nine patients and was highly hypervascular, showing viable cancer cells despite transcatheter arterial embolization in 19 patients. During the series of treatment sessions for each patient, the same concentration of acetic acid was used. Eight (89%) of nine slightly hypervascular main tumors, 18 (95%) of 19 highly hypervascular main tumors, and all 14 small tumors were treated successfully. No serious complications occurred as a direct sequela to acetic acid injection. The 1-, 2- and 3-year recurrence rate from the original main tumor was 0%, 20%, and 20%, respectively, in patients treated with percutaneous acetic acid injection alone and 12%, 24%, and 24% in patients treated with percutaneous acetic acid injection after transcatheter arterial embolization (P = NS). The 1-, 2-, 3-, 4-, and 5-year survival rates were 100%, 80%, 80%, 80%, and 0%, respectively, in the former and 90%, 81%, 81%, 61%, and 61% in the latter (P = NS). Percutaneous acetic acid injection (15% to 50%) may be an effective therapy for slightly hypervascular nodular HCCs larger than 3 cm and highly hypervascular nodular HCCs larger than 3 cm that remain partly viable after transcatheter arterial embolization.