OBJECTIVES: In elderly patients with atrial fibrillation (AF), medial temporal lobe (MTL) atrophy and white matter lesions (WML) may account for the cognitive decline. Though a combination therapy of statins with cholesterol lowering agents like ezetimibe may be beneficial in patients with AF, its effects on MTL structure and WML remains unknown. METHODS: A parallel group double-blinded randomized trial was performed during 1 year whereby elderly stroke-free AF patients either received placebo or atorvastatin and ezetimibe on top oral anticoagulation therapy. Neuropsychological performance and inflammatory markers in the blood were assessed at baseline and 1 year later together with amygdala and hippocampal volume as well as WML. RESULTS: Sixty-three patients were assessed for eligibility, but 29 patients had to be excluded so that 34 patients were randomized to both groups. In the treatment group, the systemic level of inflammation was significantly decreased after 1 year and an improvement in cognitive speed as well as short- and long-term memory was observed. While there was no significant difference in MTL volume at baseline, the placebo group exhibited more atrophy for right amygdala and left hippocampus at follow-up. Finally, descriptive data showed a slight decline of WML volume in the treatment group. CONCLUSIONS: In spite of limitations due to small sample size, our data suggest that intensive cholesterol lowering therapy in AF patients may slow cognitive decline and atrophy of the MTL. Though these results have to be replicated in a larger sample, they offer potential for future interventions.