[Background] Combined pulmonary fibrosis and emphysema (CPFE) frequently complicates lung cancer. Chemotherapy induced interstitial lung disease (ILD) is frequently occurs in these patients and chemotherapy is hard to undertake in such case.[Objective] The purpose of this research was to clarify the risk and prognosis of ILD in cases of unresectable non-small cell lung cancer (NSCLC) with CPFE treated by chemotherapy.[Method] We conducted a retrospective investigation of 14 patients with stage IIIB or IV NSCLC with emphysema and interstitial pneumonia detected by chest computed tomography, who were treated by chemotherapy at our hospital between April 1, 2004 and August 31, 2010. [Results] Six of the 14 patients developed ILD. High values of KL-6 (P = 0.028) measured before chemotherapy were identified as a predictor of the development of ILD.Median survival in ILD group and non ILD group was respectively 237 and 820 days.[Conclusion] Unresectable NSCLC patients with CPFE receiving chemotherapy show a high predisposition for developing ILD, especially in cases with high KL-6 values, and tend to have a poor prognosis.