Critically ill patients are at high risk of developing serious neurological dysfunctions including delirium and long-term cognitive impairment (LTCI). A growing body of evidence has shown that critical illness and its treatment can lead to de novo cerebral atrophy including white and grey matter abnormalities, delirium, and neurocognitive decline. This phenomenon is a major public health issue that effects literally millions of ICU patients each day. Cerebral atrophy is manifested in some LTCI patients over the first several months following their ICU discharge, yet no systematic or well-designed, prospective imaging studies have been conducted to date. Interestingly, of seven small studies of post-ICU LTCI performed to date, none have found a relationship between severity of illness and the development of LTCI, and none have included functional magnetic resonance imaging (fMRI), voxel based morphometry (VBM) nor diffusion tensor imaging (DTI) in evaluations of neurological dysfunction. After adjusting for severity of illness and age, delirium has been shown to be a strong independent predictor of the risk of LTCI amongst ICU survivors. The current study is a prospective, case-control pilot investigation designed to examine a cohort of ICU patients with and without delirium via magnetic resonance imaging (MRI). Cases and controls were scanned at hospital discharge and at 3-month follow-up. Results suggested a complex relationship between delirium, brain function and anatomy. Specifically, at 3-month follow-up, cases exhibited significantly lower levels of blood oxygen level (BOLD) response compared to controls, even while controlling for time-1 group differences. Moreover, cases also displayed evidence of grey and white matter atrophy, expansion of the cerebral ventricles, and attenuated axonal fractional anisotropy (FA) compared to non-delirious patients. The extent of this neurological degradation was also highly correlated with several neuropsychological measures. Clinical and theoretical implication of these data as well as future directions and questions in delirium research are discussed. This data set is planned to be used to design a larger cohort study as a competitive supplement to an ongoing NIH-sponsored R01 entitled BRAIN ICU (Bringing to light the Risk factors And Incidence of Neurological dysfunction in ICU survivors) which is being conducted between 2007 and 2011 at Vanderbilt University Medical Center (VUMC).