Background <p>We have previously reported that vitamin K dosing augments the anticancer effects of sorafenib by suppressing levels of des-γ-carboxy prothrombin, a known tumor growth and angiogenesis factor produced in HCC under sorafenib-induced ischemia. Herein, we aimed to establish whether vitamin K dosing could afford a similar anticancer effect when combined with transarterial chemoembolization (TACE).</p> Methods <p>We performed a randomized controlled trial, assigning patients with unresectable HCC (1:1) to TACE + vitamin K or TACE alone groups. Co-primary endpoints were objective response rate and PFS; the secondary endpoint was safety.</p> Results <p>The TACE + vitamin K group (<i>n</i> = 50) exhibited a significantly higher objective response rate than the TACE alone group (<i>n</i> = 51) (96.0% <i>vs</i>. 82.4%, <i>p</i> = 0.028). The PFS was significantly longer in the TACE + vitamin K group than that in the TACE alone group (median time: 262 days [95% confidence interval (CI), 35.8–488.2 days] <i>vs</i>. 146 days [95% CI, 111.6–180.4 days]; <i>p</i> = 0.013, hazard ratio: 0.55 [95% CI, 0.34–0.89]). There were no significant differences in the incidence of adverse events between groups.</p> Conclusions <p>Compared with TACE alone, vitamin K dosing combined with TACE improved anticancer outcomes.</p> Clinical trial number <p>UMIN000026404</p>