<strong>BACKGROUND</strong> The aim of this study was to examine the role of magnetic resonance imaging-diffusion weighted imaging (MRI-DWI) in the early detection of chemotherapy resistance in non-small cell lung cancer (NSCLC) patients. <strong>MATERIAL AND METHODS</strong> MRI-DWI and computed tomography (CT) were carried out in 75 patients with newly diagnostic NSCLC before and after first, second, fourth, and sixth cycles of chemotherapy. Resistance to chemotherapy was assessed based on the change in the largest tumor diameter after chemotherapy. Diffusion of water molecule in each lesion was quantitatively measured by apparent diffusion coefficient (ADC). The diagnostic results of DWI after first and second cycle of chemotherapy were analyzed by the area under receiver operating characteristics curve (ROC). <strong>RESULTS</strong> Among the patients, 43 patients were chemo-resistance while 32 patients were chemo-sensitive. The ADC changing rate between second and first cycle of chemotherapy was significantly higher in chemo-sensitive patients compared with chemo-resistance patients (t=3.236, P=0.002). The ROC showed cutoff values of the ADC changing rate after first and second cycles of chemotherapy for resistance/sensitive discrimination were 23.6% and 5.56%, respectively. DWI after first and second cycles of therapy showed sensitivities of 55.8% and 55.8%, specificities of 65.6% and 87.5%, and area under ROC of 0.568 and 0.733, respectively. <strong>CONCLUSIONS</strong> ADC changing rate between first and second cycles of chemotherapy could sensitively distinguish chemo-sensitive and chemo-resistant tumors at earlier stages, which may direct treatment adjustment and improve the prognosis of patients.