The most common pulmonary disorder induced by methotrexate is a gradually developing interstitial pneumonitis. The associated clinical manifestations include slowly progressive dyspnea and nonproductive cough, with extensive radiographic changes. One case has been reported following intrathecal methotrexate administration; the remainder occurred after either intravenous or oral therapy. We report two cases of rapidly developing respiratory distress following the administration of methotrexate into the cerebrospinal fluid. The clinical courses, radiologic findings, and, in one patient, the pathologic nature, are consistent with noncardiogenic pulmonary edema.