<p>Enfortumab vedotin, an antibody-drug conjugate, in combination with pembrolizumab (PEM) (EVP), has become a standard first-line regimen for patients with locally advanced or metastatic urothelial carcinoma (la/mUC). Although this combination demonstrates superior survival outcomes compared with platinum-based chemotherapy, interstitial pneumonitis has been reported in up to 10% of cases. Acute, fatal presentations, however, are exceedingly rare. We report the case of a 78-year-old man with mUC and asymptomatic interstitial lung disease, identified on baseline chest computed tomography (CT), who developed rapidly progressive and fatal drug-induced interstitial pneumonitis after three cycles of EVP. His comorbidities included diabetes mellitus, obesity, and hypertension. On day 17 of the third cycle, he presented with dyspnea, and CT of the chest demonstrated diffuse bilateral ground-glass opacities. Despite the prompt initiation of high-dose corticosteroids and broad-spectrum antimicrobials, respiratory failure progressed rapidly, and the patient died 5&#xa0;days after symptom onset. Compared with prior studies, the clinical course was exceptionally fulminant and refractory to treatment. Advanced age, poorly controlled diabetes mellitus, obesity, and pre-existing interstitial lung disease may have contributed to the severe outcome, emphasizing the need for careful patient selection and rigorous respiratory monitoring when administering EVP.</p>