Background: Methotrexate is an antimetabolite drug that blocks dihydrofolate reductase and impairs cellular DNA synthesis. Administration of intravenous iodinated radiocontrast agents can cause life-threatening toxicity in patients receiving methotrexate. Case: A 60-year-old female patient with rheumatoid arthritis underwent a craniotomy and clipping of a distal anterior cerebral artery aneurysm. The patient had been on low-dose oral methotrexate for the previous 5 years, which was discontinued two days before surgery. The patient received the first intravenous contrast agent injection (iohexol) during diagnostic cerebral angiography one day prior to surgery (50 ml) and the second contrast dose on the first postoperative day (60 ml). The patient developed severe methotrexate toxicity, leading to fatal multiorgan failure and death following repeated contrast imaging with intravenous iohexol. Conclusions Even though low-dose oral methotrexate has minor adverse effects, life-threatening toxicity can be precipitated in the presence of iodinated contrast agents.