The objective of this investigation is to review existing research pertaining to cognitive impairment and decline following critical illness and describe a case involving a 49-year-old female with sepsis and acute respiratory distress syndrome (ARDS) with no prior neurologic history who, compared to baseline neuropsychological test data, experienced dramatic cognitive decline and brain atrophy following treatment in the medical intensive care unit (ICU) at Vanderbilt University Medical Center. The patient participated in detailed clinical interviews and underwent comprehensive neuropsychological testing and neurological magnetic resonance imaging (MRI) at approximately 8 months and 3.5 years after ICU discharge. Compared to pre-ICU baseline test data, her intellectual function declined approximately 2 standard deviations from 139 to 106 (from the 99 to the 61 percentile) on a standardized intelligence test 8 months post-discharge, with little subsequent improvement. Initial diffusion tensor brain magnetic resonance imaging (DT-MRI) at the end of ICU hospitalization showed diffuse abnormal hyperintense areas involving predominately white matter in both hemispheres and the left cerebellum. A brain MRI nearly 4 years after ICU discharge demonstrated interval development of profound and generalized atrophy with sulcal widening and ventricular enlargement. The magnitude of cognitive decline experienced by ICU survivors is difficult to quantify due to the unavailability of pre-morbid neuropsychological data. The current case, conducted on a patient with baseline neuropsychological data, illustrates the trajectory of decline occurring after critical illness and ICU-associated brain injury with marked atrophy and concomitant cognitive impairments.