Genetic variables are thought to interact with environmental factors, such as alcohol exposure history, to produce individual differences in alcohol abuse and alcoholism. The objective of this study was to test the potential interaction between genetic predisposition to consume alcohol and alcohol pretreatment on subsequent self-administration. To accomplish this goal, four groups of mice from the ethanol-avoiding DBA/2J (D2) and ethanol-preferring C57BL/6J (B6) inbred strains were exposed to saline, acute ethanol (2 g/kg), or chronic intermittent ethanol (1 or 2 g/kg) intraperitoneal (i.p.) injections. Locomotor activity was monitored after each injection. After preexposure, animals were given a two-bottle choice test with various concentrations of ethanol/sucrose vs. sucrose or ethanol vs. water for 4 days at each concentration. Then, all animals were challenged with a 2.0 g/kg ethanol i.p. injection and locomotor activity was assessed. Acute and chronic ethanol pretreatment increased locomotor activity in response to a challenge dose of ethanol (2 g/kg) in D2 mice but had no effect on B6 mice. Prior exposure to ethanol altered the amount of ethanol consumed in a mouse strain-dependent manner. D2 mice showed a positive relationship between ethanol intake and dose or duration of ethanol preexposure. B6 mice preexposed to ethanol consumed more ethanol than naive animals, independent of dose or duration of exposure. During the last phase of self-administration testing, D2 mice exposed to chronic ethanol (2 g/kg) consumed as much ethanol as B6 from the same pretreatment condition. After a history of ethanol self-administration, saline control mice from the D2 strain showed equal locomotor activation as compared to D2 mice that were pretreated with ethanol injections. B6 mice showed no change in locomotor activity after ethanol self-administration or injection. These results demonstrate that genetic predisposition to avoid alcohol (D2 mice) can be modified by a history of preexposure and that a predisposition to prefer alcohol (B6 mice) may be also amenable to influence by drug history. In general, the results of this study suggest that genetic factors may interact with previous exposure to ethanol to modify ethanol self-administration.