Considering the existing interactions between ethanol and adenosine, the influence of the genetic impairment of the adenosine A_2A receptor has been examined upon the seizures occurring at the cessation of chronic ethanol intake or ‘ethanol withdrawal’ in male mice. Acute clearance of ethanol did not differ between adenosine A_2A receptor knockout and wild-type mice. Mice were exposed for 10 days to a diet consisting of a milky chocolate drink that contained increasing concentrations (1.8, 3.6 and 6.3% v/v) of ethanol. Adenosine A_2A receptor knockout mice ingested similar amounts of the fluid, either containing alcohol or not, as did the controls. The severity of handling-induced convulsions during withdrawal was significantly reduced in the adenosine A_2A receptor knockout mice as compared with their wild-type controls. The selective adenosine A_2A receptor antagonist ZM 241385 (20 mg/kg) also significantly attenuated the intensity of withdrawal-induced seizures occurring in wild-type male mice when intraperitoneally administered twice daily during the last 5 days of the forced alcohol intake. These results suggest that selective adenosine A_2A receptor antagonists may be useful in the treatment of alcohol withdrawal.