The liver resection for solitary large hepatocellular carcinoma (SLHCC) remains controversial due to the high risk of complications and recurrence after resection. This study aimed to compare the efficacy and safety of transcatheter arterial chemoembolization (TACE) plus microwave ablation (MWA) with resection for SLHCC.We retrospectively analyzed a total of 148 patients who were treated with either TACE-MWA (n = 94) or resection (n = 54) for SLHCC (≥5 cm). A matched cohort composed of 86 patients was included after propensity score matching (PSM). The primary endpoint was overall survival (OS), and the secondary endpoints were progression-free survival (PFS) and safety.The TACE-MWA group was older with higher ALT and AST (all P < 0.05). After PSM, the 1-, 3-, and 5-year OS were 100%, 80.3%, and 51.0% in the TACE-MWA group, and 88.3%, 66.7%, and 39.4% in the liver resection group, respectively. The 1-, 3-, and 5-year PFS were 76.7%, 48.8%, and 19.6% in the TACE-MWA group, and 72%, 40.2%, and 22.6% in the liver resection group, respectively. There was no significant difference in OS and PFS between the two groups (all P > 0.05). For SLHCC patients with tumor size ≥7cm, TACE-MWA showed favorable OS than liver resection. The TACE-MWA group exhibited a lower rate of major complications and shorter hospital stay than the resection group.TACE-MWA showed comparable efficacy to liver resection in patients with SLHCC, but better safety and shorter hospital stay. TACE-MWA might provide a longer OS than liver resection for SLHCC patients with tumor size ≥7cm.© 2022 Zhang et al.