Patients with probable Alzheimer's disease and depressive patients frequently present with subjective memory complaints. Objective distinction of underlying neuronal substrate malfunction and early cross-sectional differential diagnosis have been elusive thus far. We used repetitive learning and free recall of abstract geometric patterns during functional magnetic resonance imaging to assess episodic memory in older subjects (ages 56-64 years) who sought first-time medical attention with subjective memory complaints and were diagnosed with probable Alzheimer's disease (NINCDS-ADRDA criteria; ages 51-67 years) or major depressive disorder (DSM-IV; ages 50-65 years). Contrasting healthy seniors or depressive patients with Alzheimer's disease patients revealed superiority of hippocampal activation. Contrasting Alzheimer's disease patients with seniors showed bilateral prefrontal activity as a correlate of futile compensation of episodic memory failure. Contrasting patients who had major depressive disorder with seniors or patients who had Alzheimer's disease showed bilateral activation of the orbitofrontal cortex and the anterior cingulate. Subjective memory complaints may be classified objectively and very early with functional magnetic resonance imaging of episodic memory in groups of patients with Alzheimer's disease and depressive syndrome. This may facilitate drug trials with evaluation of specific treatments, but further studies will be needed to establish the differential diagnosis for the individual patient.