5-Fluorouracil (5-FU), a commonly used antimetabolite and antineoplastic agent, has been approved for treatment of various cancers. Neurotoxicities are considered extremely rare side effects of 5-FU. We present a case of 5-FU-induced encephalopathy with diffusion-restricted reversible lesion of the splenium of the corpus callosum in a patient with colorectal cancer. The patient presented with confusion, dysarthria and agitation after 5-FU infusion. The prognosis of this toxic effects of 5-FU is usually good if recognised and treated in time. Emergency physicians, general practitioners and oncologists should be aware of this rare side effects of 5-FU chemotherapy and its diagnosis and treatment.