Preoperative assessment of the acquired resistance T790M mutation in patients with metastatic non-small cell lung cancer (NSCLC) based on brain metastasis (BM) is important for early treatment decisions. To investigate preoperative magnetic resonance imaging (MRI)-based radiomics for assessing T790M resistance mutation after epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) treatment in NSCLC patients with BM. Retrospective. One hundred and ten primary NSCLC patients with pathologically confirmed BM and T790M mutation status assessment from two centers divided into primary training (N=53), internal validation (N=27), and external validation (N=30) sets. Contrast-enhanced T1-weighted (T1CE) and T2-weighted (T2W) fast spin echo sequences at 3.0 T. Forty-five (40.9%) patients were T790M-positive and 65 (59.1%) patients were T790M-negative. The tumor active area (TAA) and peritumoral edema area (POA) of BM were delineated on pre-treatment T1CE and T2W images. Radiomics signatures were built based on features selected from TAA (RS-TAA), POA (RS-POA), and their combination (RS-Com) to assess the T790M resistance mutation after EGFR-TKI treatment. Receiver operating characteristic (ROC) curves were used to assess the capabilities of the developed RSs. The area under the ROC curves (AUC), sensitivity, and specificity were generated as comparison metrics. We identified two features (from TAA) and three features (from POA) that are highly associated with the T790M mutation status. The developed RS-TAA, RS-POA, and RS-Com showed good performance, with AUCs of 0.807, 0.807, and 0.864 in the internal validation, and 0.783, 0.814, and 0.860 in the external validation sets, respectively. Pretreatment brain MRI of NSCLC patients with BM might effectively detect the T790M resistance mutation, with both TAA and POA having important values. The multi-region combined radiomics signature may have potential to be a new biomarker for assessing T790M mutation. 3 TECHNICAL EFFICACY: Stage 2.