Cancer patients often develop anorexia during the course of cancer chemotherapy. It is known that daytime sleepiness is also the major complaints made by cancer patients, and this sleep problem can worsen anorexia. Previous studies reported the histamine H₃ receptor as a target for treating sleep disorders, and selective H₃ receptor inverse agonists are effective at reducing daytime sleepiness. In this study, we investigated the involvement of the H₃ receptor in the development of chemotherapy-induced anorexia in mice. Cisplatin (7.5 mg/kg, i.p.) induced anorexia within 24 hours of its administration and it continued for 3 days, and daily administration of an H₃ receptor inverse agonist (ciproxifan, 1 mg/kg, s.c.) significantly inhibited the development of anorexia. Daily administration of an orexin 2 receptor agonist (YNT-185, 20 mg/kg, s.c.), which was reported to induce wakefulness in mice and to activate the histaminergic system, also inhibited the cisplatin-induced anorexia, and its inhibitory effects were antagonized by daily administration of an H₃ receptor silent antagonist (VUF5681, 5 mg/kg, s.c.). These results suggest that sleep problem may contribute to the development of cisplatin-induced anorexia in mice, and H₃ receptor inverse agonists have the potential to be candidates used as its treatment.