PURPOSE: To prospectively assess abnormalities in brain activation patterns during encoding and retrieval in subjects with mild cognitive impairment by using 4-T functional magnetic resonance (MR) imaging. MATERIALS AND METHODS: The institutional review board approved this HIPAA-compliant study; all subjects gave written informed consent. Twenty patients with mild cognitive impairment (12 men, eight women; mean age, 75.0 years +/- 7.6 [standard deviation]) and 20 elderly control subjects (nine men, 11 women; mean age, 71.2 years +/- 4.5) underwent functional MR imaging at 4 T during a novel-versus-familiar face-name encoding-retrieval task. The magnitude of blood oxygen level-dependent brain responses across the entire brain were compared within and between subjects with mild cognitive impairment and control subjects by using a voxelwise random-effects model. A one-sample t test was used for within-group analysis; an analysis-of-covariance model (with age as a covariate) was used for between-group analysis. RESULTS: Brain regions activated by the task (prefrontal, medial temporal, and parietal regions) during encoding were similar to those activated during retrieval, with larger areas activated during retrieval. Subjects with mild cognitive impairment showed decreased magnitude of activation in bilateral frontal cortex regions (during encoding and retrieval), the left hippocampus (during retrieval), and the left cerebellum (during encoding) compared with magnitude of activation in control subjects (P < .001). Patients with mild cognitive impairment showed increased activation in the posterior frontal lobes (during retrieval) (P < .001). Lower hippocampal activation during retrieval was the most significant correlate of clinical severity of memory loss in mild cognitive impairment (P < .001). CONCLUSION: A difference exists in the response of brain regions underlying encoding and retrieval in mild cognitive impairment. Memory deficits in mild cognitive impairment may be linked to functional alterations in several specific brain regions both inside and outside the medial temporal lobe.