 Pematrexed, PM, a novel multi-targeted antifolate agent, is used as a chemotherapeutic drug for the treatment of various types of cancer, including non-small cell lung cancer and SCLC. Despite its efficacy, it is associated with a high incidence of acute kidney injury, A.K.I., which can lead to renal failure if left untreated. In these two cases, both patients experienced A.K.I. following PM treatment, despite no evidence of acute tubular necrosis being found in either case. Furthermore, both patients also suffered from myelosuppression, suggesting that the A.K.I. could have been caused by the combination of PM and the concurrent use of folic acid and vitamin B12 supplements. This article was authored by Tito Zadre, Francesco Laundrino, Matteo Tretzi, and others.