Male C57BL/6N (C57) and DBA/2N (DBA) inbred mice were found to differ in open-field behavior after an acute ip injection of ethanol and in the development of tolerance to repeated injections. DBA mice showed only increased activity for 28 min after ethanol doses up to 2.67% g/kg when compared with saline-injected controls. Under the same conditions, C57 mice showed dose-related increases in activity during the first 4 min, followed by dose-related decreases in activity. The effects endured for at least 60 min after injection in both strains. In a third experiment, mice were injected daily with saline or 2.0 g/kg ethanol and tested on Days 1, 5, 9, and 13 for open-field activity. On the 17th day, all mice were tested after an ethanol injection. Neither strain showed tolerance to the activity-stimulating effect of ethanol. Some evidence for tolerance to the effect of ethanol to reduce activity in C57 mice was found. In a fourth experiment, twice-daily injections of ethanol for 10 days produced marked tolerance to the depressant effect of an injection on the 11th day in C57 mice, compared with those in a control group given ethanol for the first time on the 11th day. No tolerance to the stimulant effect of ethanol was seen in C57s. DBA mice were injected twice daily for 19 days but did not display tolerance when tested on Day 10 or on Day 20, Indeed, DBA mice chronically treated with ethanol exhibited more marked stimulation of activity after ethanol than mice treated chronically with saline. Differences in blood ethanol concentrations between the strains could not account for any of the observed differences. Implications for the genetic control of responses to ethanol are discussed.