The aims of this study were to assess the cognitive effects of depression reduction and sertraline treatment in patients with Alzheimer's disease (AD) and major depression. Forty-four patients with probable AD and major depression were enrolled in a double-blind, placebo-controlled, clinical trial of sertraline. Cognitive testing was performed at baseline and at 3-week intervals throughout the 12-week study. Results indicated that neither improved mood nor use of sertraline was associated with cognitive change over the trial. Post-hoc exploration of the data suggested a sex difference such that women treated with sertraline demonstrated improved cognition compared to women on placebo, whereas men treated with sertraline worsened significantly in cognition compared to men on placebo. Cognitive functioning in patients with AD and depression did not improve after successful treatment of depressed mood. The suggestion that the cognitive functioning of women with AD and depression benefits from sertraline warrants further investigation.