Rupture of hepatocellular carcinoma (HCC) releases tumor cells and furthers peritoneal metastasis. The present study investigated the killing effects of distilled water (DW) on HCC cells and the clinical outcomes of patients undergoing liver resection with DW lavage for spontaneously ruptured HCC. Human HCC cells (BEL-7402, SMMC7721) were treated with DW, the morphological changes observed, and cell viability measured. DW-treated HCC cells were also injected intraperitoneally into nude mice, and the formation of tumor nodules and overall survival (OS) measured. The clinicopathological data of 141 consecutive patients undergoing liver resection for spontaneously ruptured HCC during 1998-2011 were retrospectively reviewed. Fifteen minutes of DW exposure caused complete cell lysis of HCC cells in vitro and completely prevented tumor formation and prolonged survival time in nude mice. Among the 141 patients, the 1-, 3-, and 5-year disease-free survival (DFS) and OS rates in patients administered DW lavage during surgery were 68.9, 24.6, and 6.6 %, respectively, and 95.1, 65.1, and 40 %, respectively, which were significantly higher than those in patients who did not (P < 0.05). DW lavage was an independent predictor of recurrence (odds ratio (OR), 0.34; 95 % confidence interval (CI), 0.23-0.51; P < 0.001) and OS (OR, 0.35; 95 % CI, 0.23-0.53; P < 0.001). Fifteen minutes of DW lavage can effectively kill HCC cells in vitro and prevent tumor formation in vivo. DW lavage significantly improves long-term outcomes in patients undergoing liver resection for spontaneously ruptured HCC and could be administered intra-operatively when tumor cell liberation is suspected.