Acute encephalopathy is a change in the level of consciousness where the underlying etiology can be difficult to diagnose, and thus, difficult to treat, especially in the context of multi-organ diseases. We report a case of acute encephalopathy in a patient with end-stage renal disease (ESRD) on hemodialysis, chronic hypotension, and a recent diagnosis of colon cancer who presented shortly after initiation of FOLFOX, a chemotherapy regimen for treatment of colorectal cancer comprised of folinic acid (leucovorin), fluorouracil (5-FU), and oxaliplatin (eloxatin). We present a systematic approach to elucidate ambiguous causes of toxicmetabolic encephalopathy.