Heart failure (HF) patients exhibit enhanced sympathetic tone, aberrant responses to blood pressure challenges, and sleep-related breathing disorders, suggesting that the syndrome is accompanied by central neural deficits. We assessed regional gray matter volumes over the entire brain in nine HF patients (51 +/- 10 yr; left ventricular ejection fraction 0.27 +/- 0.06; six men) and 27 healthy controls (46 +/- 12 yr; 22 men) using T1-weighted magnetic resonance imaging to evaluate potential neural damage. Regional volumes were evaluated by using voxel-based morphometry while controlling for age, gender, and handedness. HF patients showed significant and largely lateralized gray matter loss in autonomic and respiratory-related areas as well as regions not classically associated with such control, including the insula and basal ganglia, right cingulate gyrus, parahippocampal/fusiform gyrus, dorsal midbrain extending to the posterior and medial thalamus, ventral and superior lateral frontal cortex, bilateral cerebellar quadrangular lobules and right fastigial and neighboring nuclei, and bilateral deep parietal and lateral parietal-occipital cortex. Areas of gray matter loss may contribute to inappropriate cognitive, autonomic, and breathing regulation in HF.