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Objective: Findings on spatial memory in depression have been inconsistent. A navigation task based on virtual reality may provide a more sensitive and consistent measure of the hippocampal-related spatial memory deficits associated with depression. Method: Performance on a novel virtual reality navigation task and a traditional measure of spatial memory was assessed in 30 depressed patients (unipolar and bipolar) and 19 normal comparison subjects. Results: Depressed patients performed significantly worse than comparison subjects on the virtual reality task, as assessed by the number of locations found in the virtual town. Between-group differences were not detected on the traditional measure. The navigation task showed high test-retest reliability. Conclusions: Depressed patients performed worse than healthy subjects on a novel spatial memory task. Virtual reality navigation may provide a consistent, sensitive measure of cognitive deficits in patients with affective disorders, representing a mechanism to study a putative endophenotype for hippocampal function.