The ability of the two opioid receptor-like receptor 1 (ORL1) agonists nociceptin (5 nmol i.c.v.) and synthetic (1S,3aS)-8-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one hydrochloride (Ro 64-6198; 0.1, 0.3, and 1.0 mg/kg i.p.) and the opioid antagonist naloxone (0.1, 1.0, and 10.0 mg/kg s.c.) to modify ethanol-induced conditioned place preference was examined in NMRI male mice. The ORL1 agonists were found to significantly reduce the acquisition, expression, and ethanol-induced reinstatement of conditioned place preference. Unlike the ORL1 agonists, naloxone at the doses relevant for opioid receptor blockade failed to significantly influence the acquisition of ethanol-induced conditioned place preference. However, naloxone at 1.0 but not 0.1 mg/kg s.c. potently blocked the expression of ethanol-induced conditioned place preference and significantly inhibited ethanol-induced reinstatement of the conditioned place preference after extinction. Separate experiments indicated that nociceptin and Ro 64-6198 are both devoid of reinforcing or aversive properties. Naloxone, however, at 1.0 and 10.0 mg/kg, produced conditioned place aversion, indicating motivational properties of its own. Both nociceptin and Ro 64-6198 reduced locomotor activity after acute administration. However, tolerance developed very quickly to this effect and already after three i.c.v. (or i.p.) injections, there was no significant reduction of locomotor activity. It is concluded that ORL1 agonists can modulate the acquisition, expression, and reinstatement of the conditioned reinforcing effects of ethanol with no reinforcing or aversive properties of their own. This property might be a potential advantage in the treatment of alcoholism compared with nonselective opioid antagonist naltrexone.