Background: The role of surgical resection for patients with single large (≥ 5cm) and/or multinodular (≥ 2)hepatocellular carcinoma (HCC) is still controversial. This systematic review was performed to evaluate thesafety and efficacy of resection for patients with single large and/or multinodular HCC. Materials and Methods:Databases (the PubMed, Web of Science, Embase, and Cochrane databases) were systematically searched toidentify relevant studies exploring the safety and efficacy of resection for single large and/or multinodular HCC,published between January 2000 and December 2014. Perioperative morbidity and mortality, overall survival,and disease-free survival of the resection group were calculated. In addition, these outcome variables were alsocalculated for the control group in the included studies. Results: One randomized controlled trial and 42 nonrandomizedstudies involving 9,580 patients were eligible for analysis. Eight (1,594 patients) of the 43 studiesalso reported the outcomes of transarterial chemoembolization (TACE). Although 51.4% of patients featuredcirrhosis, 90.7% of them demonstrated Child-Pugh A liver function in the resection group. The median ratesof morbidity (24.5%) and mortality (2.5%) after resection were significantly higher than that of TACE (11.0%,P<0.001; 1.9%, P<0.001). However, patients who underwent resection had significantly higher median one-,three-, and five-year overall survival (76.1%, 51.7%, and 37.4%) than those who underwent TACE (68.3%,31.5%, and 17.5%, all P<0.001). The median 1-, 3-, and 5-year DFS rates after resection were 58.3%, 34.6%, and24.0%, respectively. Conclusions: Although tumor recurrence after resection for patients with single large and/or multinodular HCC continues to be a major problem, resection should be considered as a strategy to achievelong-term survival.