AbstractAimWe evaluated the safety and efficacy of vascular endothelial growth factor receptor (VEGFR)‐targeted peptide vaccines for the immunization of patients with unresectable hepatocellular carcinoma (HCC) who had responded to transarterial chemoembolization.MethodsTwenty‐two patients were randomized 1:1 to receive VEGFR‐targeted peptides or placebo. The primary end‐point was the safety assessment of the immunization. The secondary end‐points were evaluation of immunological responses and clinical outcomes.ResultsNo severe adverse events were induced by the study agents. Among the 12 patients in the vaccine group, a VEGFR1‐specific cytotoxic T lymphocyte (CTL) response was induced in eight (66.7%) patients and a VEGFR2‐specific CTL response was induced in 10 (83.3%). The median progression‐free survival (PFS) and overall survival (OS) rates were 4.8 and 52.0 months, respectively, in the vaccine group, and 2.7 and 21.8 months, respectively, in the placebo group. No statistically significant differences were found between the two groups (PFS p = 0.925, OS p = 0.190). When divided into two groups according to immunoreactivity, the median PFS of patients with and without a strong immune response to VEGFR1 were 7.4 and 2.7 months, and that to VEGFR2 were 10.6 and 2.7 months, respectively; there were significant differences according to the immune response.ConclusionsImmunotherapy with peptide vaccines targeting VEGFR1 and VEGFR2 was well tolerated with no serious adverse events. It also effectively induced peptide‐specific CTLs in patients with unresectable HCC.