Sensitization to the locomotor‐stimulant effects of drugs is thought to play an important role in the development of drug‐seeking behaviour. We hypothesized that the ability of acamprosate to reduce alcohol relapse rates in recovering alcoholics, and alcohol consumption in rodents, may be related to its ability to reduce sensitization to the locomotor‐stimulant effects of alcohol. The purpose of the present study was to determine whether acamprosate reduces the expression of sensitization to the locomotor‐stimulant effects of alcohol in lines of mice selectively bred for high (HAP) and low (LAP) alcohol preference. Mice were given six intraperitoneal (i.p.) injections of alcohol (3 g/kg) or saline at 48 h intervals. The test for sensitization to the locomotor‐stimulant effects of alcohol consisted of a challenge dose of 2 g/kg i.p. alcohol followed immediately by assessment of locomotor activity for 20 min. Mice were pretreated with either saline or acamprosate (400 mg/kg) at 14 h and again at 2 h before the alcohol challenge. Both HAP and LAP mice showed sensitization to the locomotor‐stimulant effects of alcohol. Acamprosate reduced the expression of sensitization to the locomotor‐stimulant effects of alcohol in HAP but not LAP mice. These data suggest complex effects of acamprosate on alcohol‐stimulated locomotor activity that depend on genotype.