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Introduction Methotrexate is administered through different routes to treat childhood acute lymphoblastic leukemia. Toxicities of low, intermediate, or high doses of methotrexate have been described in the literature. Methotrexate-induced or related pneumonitis is a rare complication that leads, in most cases, to discontinuing this drug. Case report We report a case of a 17-year-old female patient with newly diagnosed B-acute lymphoblastic leukemia who received a high-dose methotrexate on an induction course. Eight days after methotrexate infusion, she developed fever, dyspnea, hypoxemia, and dry cough. Chest computed tomography showed mosaic attenuation of lung parenchyma and bilateral interstitial infiltrate in favor of hypersensitivity pneumonitis with no evidence of bacterial or fungal infections. Management and outcome Methotrexate-related pneumonitis was diagnosed and corticosteroids were prescribed. Improvement of the symptomatology was noted within four days. Given the importance of methotrexate in the treatment of acute lymphoblastic leukemia, intrathecal methotrexate was administered without incident and high-dose methotrexate was re-introduced successfully two and a half months after the pneumonitis episode while using corticosteroids. According to Naranjo's algorithm, the reaction to the drug was found to be probable with a score of 6. Discussion Methotrexate is the backbone of acute lymphoblastic leukemia treatment, but numerous adverse reactions have been published of which methotrexate pneumonitis can be fatal in some cases. In this case, we concluded that this drug can be successfully reintroduced after methotrexate-related pneumonitis.