Background: The prognostic significance of serosal invasion (SI) was not clarified in patients with hepatocellular carcinoma (HCC). We investigated the impact of serosal invasion (SI) for the long-term outcome after curative surgical resection in patients with HCC. Methods: In total, 783 consecutive patients with HCC who underwent curative surgical resection without any preoperative treatment were histologically evaluated for SI. Patients with SI were classified into two groups: positive for SI (pSI; n=333) and negative for SI (nSI; n=450). Clinicopathologic features, disease-free survival (DFS), and overall survival (OS) were compared between patients with pSI and nSI. Results: The pSI group showed more aggressive tumor characteristics, such as higher tumor marker levels (alpha-fetoprotein, P=.023; protein induced by vitamin K absence-II, P=.016), larger tumor size (P<.001), higher prevalence of microvascular invasion (P=.002), and poorer differentiation (P=.002), than the nSI group. In survival analysis, 5-year DFS was 48.1%, 61.2% in the pSI, nSI, respectively (P<.001), while 5-year OS was 74.8%, 86.1%, respectively (P=.002). In multivariate analysis, SI was an independent prognostic factor for DFS (P=.043) and OS (P=.042). Conclusions: The SI was associated with more aggressive clinicopathologic characteristics and a higher risk of poor survival. Therefore, intensive careful follow-up is essential for patients with pSI after curative surgical resection in patients with HCC.