Abstract The present study evaluated the extension of a new rat model of depression, repeated open-space swimming, which overcomes drawbacks of existing models, to mice. Mice were swum for 15 min daily in a large tank of tepid water for 4 days and thereafter at 4 day intervals for a period of 3 weeks. Some of the animals were provided with an active coping (escape) response. Variables measured included time floating, distance swum, immobility on a subsequent tail-suspension test, sucrose preference and brain cell proliferation (Ki67 immunohistochemistry) as well as responses to 2 antidepressant drugs, desmethylimipramine and fluoxetine, and 2 non-antidepressant drugs, haloperidol and diazepam. The repeated swims were found to increase time floating and tail-suspension immobility and to decrease distance swum, sucrose preference and brain cell proliferation. Both chronic antidepressant drugs as well as the active coping response attenuated the increased time floating while neither of the non-antidepressant drugs had this effect. The distance swum measure was found to be more variable. Chronic fluoxetine also reversed the increased tail-suspension immobility, reduced sucrose preference and reduced brain cell proliferation caused by the model. It is concluded that repeated open-space swim represents a useful new model of depression in the mouse.