Introduction Pemetrexed is a folate antimetabolite chemotherapy agent widely used in the treatment of non-small cell lung cancer and malignant pleural mesothelioma. While generally well-tolerated with appropriate supportive measures (folic acid, vitamin B12), pemetrexed carries a risk of hematologic, renal, and gastrointestinal toxicity. Nonsteroidal anti-inflammatory drugs (NSAIDs), commonly used for pain and inflammation, can significantly increase the toxicity of pemetrexed. This interaction is particularly concerning in patients with reduced renal function. The mechanism involves pharmacokinetic interference, leading to higher systemic exposure to pemetrexed, which amplifies its adverse effects. Understanding this interaction is vital to prevent complications and ensure safe and…