BACKGROUND AND AIMS: Interstitial pneumonitis is a potentially fatal complication of cancer-related therapy. However, data regarding the risk factors, prognosis and safety and benefit of rechallenge treatment are scarce. METHODS: Patients diagnosed with pancreatic cancer were retrospectively enrolled, and those with pneumonitis were identified. We investigated the incidence and etiology of pneumonitis, potential risk factors, and impact of treatment rechallenge on clinical outcomes. RESULTS: A total of 809 patients were diagnosed with pancreatic cancer, among whom 62 (7.7%) were diagnosed with interstitial pneumonitis. Risk factors identified through competing risk analysis included nab-paclitaxel, gemcitabine, erlotinib, and previous lung diseases such as pre-existing ILD, asthma, chronic obstructive pulmonary disease, tuberculosis, primary lung cancer, metastasis, or pneumonia. Among these patients, 33 experienced acute respiratory distress syndrome, resulting in 15 deaths during pneumonitis episodes. After rechallenge therapy in 33 patients, pneumonitis recurred in 3 (9%). The median overall survival was longer in patients with pneumonitis than in those without. Subgroup analysis further revealed that overall survival was significantly better in the rechallenge group. CONCLUSIONS: Most cases of pneumonitis are not directly induced by cancer therapy. Therefore, treatment rechallenge is considered a reasonable approach, potentially resulting in improved survival outcomes.