Objective: To investigate the efficacy and feasibility of percutaneous microwave ablation (PMWA) in treatment of relatively large hepatocellular carcinoma (HCC). Methods: The clinical and follow-up data of 49 patients with unresectable and relatively large (5~6 cm) HCC who underwent ultrasound-guided PMWA from January 2007 to January 2010 were reviewed. The complete ablation (CA) rate, incidence of severe complications, overall survival rate (OS), and disease-free survival rate (DFS) as well as prognostic factors for OS of the patients were analyzed. Results: Of the 49 patients, the CA rate after initial PMWA was 85.7%, and CA was achieved in all cases after a second session of PMWA. The incidence of severe complications was 8.1%. At the end of follow-up (median follow-up time was 48 months), intrahepatic recurrence occurred in 41 cases (87.5%), the average survival time was (54.4±32.0) months, and the 1-, 3- and 5-year OS was 87.8%, 63.3% and 39 .1%, respectively; the average DFS time was (35.8±30.6) months and the 1-, 3- and 5-year DFS was 69.4%, 40.9% and 21.8%, respectively. Univariate analysis showed that preoperative positive quantitative HBV DNA and high level of alpha fetoprotein (AFP) were unfavorable factors for OS (both P<0.05), and multivariate analysis showed that preoperative high AFP level was independent influential factor for OS (HR=1.730, 95% CI=1.135–2.635, P=0.011). Conclusion: PMWA is a safe, feasible and effective treatment for relatively large HCC. However, the treatment of recurrence remains a challenge. High preoperative AFP level is independent factor of the OS after PMWA.