The most common combination of dependence on two drugs occurs with alcohol and nicotine, but little is known of the way in which these drugs interact in the brain. This study investigated the effects in mice of prolonged consumption of alcohol, by liquid diet, on the actions of nicotine on locomotor activity, and the influence of environmental cues on these effects. Administration of nicotine after chronic alcohol intake did not show any significant changes on first administration, but after 28 days of daily nicotine injections, nicotine produced significant locomotor stimulation and increased rearing activity in the mice which had previously received the alcohol diet, compared with the activity of animals that received the control diet. However, significantly increased locomotor activity was also seen, after the repeated nicotine administration, immediately prior to the nicotine injection, only in the mice that had previously consumed alcohol. Examination of the influence of the environment in which the activity was tested demonstrated that the effect on activity prior to injections was seen only if measurement was made in a test environment that was familiar to the animals. The results demonstrate an interaction between chronic alcohol consumption and the effects of environment on the actions of nicotine, that may have relevance to the consumption of these drugs in humans.