Orexins/hypocretins (Orx/Hcrt) are hypothalamic peptides that regulate a wide range of physiological processes and have been shown to be recruited by drugs of abuse. This study was designed to test the effect of the specific Orx/Hcrt receptor-1 (Hcrt-r1) antagonist, N-(2-methyl-6-benzoxazolyl)-N′-1,5-naphthyridin-4-yl urea (SB334867), on reinstatement elicited by ethanol (EtOH)-associated stimuli versus stimuli associated with a conventional reinforcer [i.e. SuperSac, consisting of 3% glucose and 0.125% saccharin (w/v)]. SB334867 (1–10 mg/kg, i.p.) dose-dependently reduced reinstatement induced by the EtOH- but not SuperSac-associated stimuli. These findings support a differential role of Hcrt-r1 in mediating EtOH seeking versus natural reward seeking.