Radiofrequency (RF) ablation is an alternative to percutaneous ethanol injection (PEI) for single nonsurgical hepatocellular carcinoma (HCC) and is currently used as adjuvant therapy before liver transplantation. This phase II study assesses the treatment-related complications and response rate of RF for the treatment of single HCC < or = 5 cm. Percutaneous RF was performed under conscious sedation and ultrasound (US) guidance with an electrical generator connected to a single cooled-tip electrode. Neoplastic cells in peripheral blood (reverse transcription-polymerase chain reaction for alpha fetoprotein [AFP] messenger RNA) were analyzed before and after RF. Treatment response was assessed by spiral computed tomography (CT) at 1 month and every 3 months by US or spiral CT thereafter. Thirty-two patients (20 men; age 67 +/- 4 years; 78% hepatitis C virus; 24 Child-Pugh A) with a mean tumor size of 2.8 cm (25 patients < or = 3 cm) were treated by RF (1.25 sessions; mean time, 22.1 +/- 2 minutes). Adjuvant PEI was performed in 9 cases. Complete response was achieved in 21 patients (65%), being significantly higher for HCC < or = 3 cm (76% vs. 29%, P = .03). After a median follow-up of 10 months, 8 patients showed treatment-related morbidity. Four of them (12.5%) showed biopsy-proven needle-track seeding detected between 4 to 18 months. Neoplastic seeding was related to subcapsular location (P = .009), poor differentiation degree (P = .02), and baseline AFP levels (P = .02). Thus, RF ablation with cooled-tip needle for HCC is associated with a high risk of neoplastic seeding. Iatrogenic dissemination was related to subcapsular location or an invasive tumoral pattern, and has to be considered when selecting curative treatments for HCC or adjuvant therapies before liver transplantation.