An inactivated quadrivalent influenza vaccine (QIV) was licensed in Japan in the 2015/2016 influenza season. In this prospective study, we assessed the immunogenicity and safety of the QIV. The study included 78 subjects aged 23–60 years. Immunogenicity was assessed using hemagglutination-inhibition assays. Reactogenicity was assessed for 6 days after vaccination, and unsolicited adverse events were assessed for 14 days after vaccination. The seroconversion rate (SCR), seroprotection rate (SPR), and geometric mean titer ratio (GMR) were: 7.7%, 80.8%, and 1.4, respectively, for the A/H1N1pdm09 strain; 76.9%, 98.7%, and 6.6, respectively, for the A/H3N2 strain; 2.6%, 67.9%, and 1.4, respectively, for the B/Yamagata strain, and 3.9%, 29.5%, and 1.3, respectively for the B/Victoria strain. Therefore A/H3N2 met all the European Medicines Agency (EMA) criteria, A/H1N1pdm09 met only the SPR, and B/Victoria and B/Yamagata met none of the criteria. The most frequent adverse event was erythema/swelling (80.8%), followed by pain (73.1%), malaise (16.7%), pruritus (12.8%), myalgia (5.1%), headache (3.8%), arthralgia (3.8%), fever (1.3%), and nausea (1.3%). Our trial demonstrated that the QIV was well tolerated, but that some strains are not immunogenic, and suggests that quality improvement needs to be implemented for the QIV.