This retrospective study aimed at evaluating the long-term outcomes and prognostic factors of microwave ablation (MWA) as a first-line treatment for hepatocellular carcinoma (HCC). 221 consecutive patients receiving MWA in our center between October 11, 2010 and December 31, 2013 were enrolled. Technique effectiveness was evaluated one month post-ablation. Initial complete ablation (CA1(st)) was gained in 201 (90.95%) patients, secondary CA (CA2(nd)) in 8 (3.62%) patients and the remaining 12 (5.43%) patients suffered from incomplete ablation (IA2(nd)) after two sessions of MWA. Patients with tumor size >5 cm were less likely to gain CA1(st). Procedure-related complications were recorded and no procedure-related death occurred. 22 (10.4%) complications occurred with 8 (3.8%) being major ones. Tumor characteristics (size, number, location) do not significantly influence complication rates. After a median follow-up of 41.0 (ranging 25.0-63.5) months, the median RFS and OS was 14.0 months (95% CI: 9.254-18.746) and 41.0 months (95% CI: 33.741-48.259) respectively. Multivariate analysis identified two significant prognosticators (levels of alpha fetal protein [AFP] and gamma-glutamyl transpeptidase [GGT]) of RFS and five significant prognosticators (tumor number, tumor size, AFP, GGT and recurrence type) of OS. In conclusion, MWA provides high technique effectiveness rate and is well tolerated in patients with HCC as a first-line treatment.