There is little data availableon the nephrotoxicity of pemetrexed, a new generation antifolate agent that is increasingly used in the treatment of numerous malignant tumors. We report the observation of two patients suffering from non-small cell lung cancer who developed acute kidney injury (AKI) after administration of pemetrexed. In one case, pemetrexed was used as a single agent treatment. In the other, pemetrexed was first co-administered with cisplatin, then alone, with AKI worsening 2 months after the discontinuation of cisplatin. The two patients concomitantly developed edema of the face, which is a rare adverse side effect of pemetrexed. Renal biopsies showed acute tubular necrosis and interstitial fibrosis. In both cases, chronic kidney disease (CKD) persisted despite drug discontinuation. Herein, we discuss renal presentation, risk factors, and prognosis of pemetrexed-induced nephrotoxicity.