Vitamin K2 induces differentiation of leukemic cell lines and apoptosis of immature blasts in myelodysplastic syndrome (MDS). We recently reported a case of MDS-refractory anemia (MDS-RA) with trilineage hematologic response to oral administration of menatetrenone, a vitamin K2 analog. To determine a possible role of this agent in treatment of MDS-RA, we conducted a prospective randomized trial assessing the safety and efficacy of menatetrenone. A total of 18 consecutive patients newly diagnosed with MDS-RA were randomized to receive either 45 mg of oral menatetrenone (group 1) or no menatetrenone (group 2). Administration of menatetrenone was well tolerated. Of the nine patients in group 1 (56%), five improved with menatetrenone treatment while only one (11%) of the group 2 patients improved. Three patients (33%) showed a major response in absolute neutrophil count (ANC), two (22%) showed a major response in hemoglobin concentration, and two of the nine (22%) showed a major response in platelet count. The ANC of group 1 patients rose after treatment, while that of group 2 patients decreased slightly at follow-up after 16 weeks ( p=0.03). Significant improvement was also seen in final platelet count ( p=0.01), but not in hemoglobin concentration. Given the absence of toxicity, menatetrenone can be recommended for all patients with MDS-RA.