The neurotoxicant cuprizone has been used extensively to create a mouse model of demyelination. However, the effects on behavior of cuprizone treatment have not been previously reported. We have analyzed the behavioral changes of mice given a diet containing 0.2% cuprizone for 6 weeks followed by 6 weeks of recovery. Behavior was assessed using a range of tests: the functional observation battery, the open-field test and the rota-rod test. Concurrent with the start of demyelination, at 3 and 4 weeks of 0.2% cuprizone treatment, the animals exhibited an increase in central nervous system activity and an inhibited anxiogenic response to the novelty challenge test. At 5 weeks of treatment (the period of maximal demyelination) equilibrium was altered and sensorimotor reactivity was also affected. Further, rota-rod analysis demonstrated that the treated group had poorer motor co-ordination than control animals. This effect was not reversed 6 weeks after cuprizone withdrawal. The animals in the recovery period also exhibited difficulties in the rota-rod progressive learning task. Our results indicate that behavioral deficits follow the course of demyelination-remyelination induced by administration of 0.2% cuprizone, and that some of the changes persist even after 6 weeks on normal diet.