Crizotinib, an inhibitor of anaplastic lymphoma kinase (ALK), was approved by Food and Drug Administration (FDA) for the treatment of patients with ALK-positive non-small cell lung cancer (NSCLC) and its administration has achieved considerable success. Preclinical studies have demonstrated crizotinib in combination with radiation could enhance the inhibitory effect on ALK-positive NSCLC. Radiation pneumonitis is a dose limiting toxicity of radiotherapy, affecting its therapeutic ratio. However, the impact of crizotinib when administered in combination with thoracic radiotherapy (TRT) on the risk of pneumonitis has not been described, including both the concomitant and sequential use of radiotherapy. Patients with ALK-driven NSCLC treated with crizotinib, with or without TRT, were identified at two institutions from 2013 to 2018. Pneumonitis was diagnosed by the treating investigator and graded in real time by using Common Toxicity Criteria for Adverse Events (version 4.0). Clinical, radiologic, and pathologic features of pneumonitis were collected. Receiving both treatments within 1 month was considered concurrent and any treatment up to 9 months apart was considered sequential. We identified 214 patients who had NSCLC with an oncogenic alteration in ALK receptor and were treated with crizotinib (15 with and 209 without TRT). Among the 15 patients treated with crizotinib and TRT, 4 received concurrent therapy and 8 received sequential therapy. All 4 patients in concurrent group developed grade 2 or 3 pneumonitis at some point during crizotinib therapy. Time to onset of pneumonitis ranged from 14 days to 61 days in concurrent group. Imaging analysis was strongly consistent with lung parenchyma changes in the irradiated lung volume receiving a total dose of 15-38 Gy. Pulmonary toxicity was manageable; however, interruption of crizotinib therapy was not necessary. Three (37.5%) experienced development of a grade 2 pneumonitis in sequential group. Pneumonitis in irradiated lungs did not aggravate after crizotinib therapy in sequential group. In conclusion, this is, to our knowledge, the first report of lung toxicity after treatment with crizotinib and TRT. We observed a high incidence of pulmonary toxicity when crizotinib and concurrent TRT were administered in patients with ALK-positive NSCLC. Careful consideration and monitoring for pneumonitis may be warranted in patients treated with crizotinib in concurrent with TRT. In addition, using other schedules (e.g., sequential as opposed to concurrent administration) may be safe and optimal strategies.