Abstract Accurate prediction of bone metastasis-free survival (BMFS) after complete surgical resection in patients with non-small cell lung cancer (NSCLC) may facilitate appropriate follow-up planning. The aim of this study was to establish and validate a preoperative CT-based deep learning (DL) signature to predict BMFS in NSCLC patients. We performed a retrospective analysis of 1547 NSCLC patients who underwent complete surgical resection, followed by at least 36 months of monitoring at two hospitals. We constructed a DL signature from multiparametric CT images using 3D convolutional neural networks, and we integrated this signature with clinical-imaging factors to establish a deep learning clinical-imaging signature (DLCS). We evaluated performance using Harrell’s concordance index (C-index) and the time-dependent receiver operating characteristic. We also assessed the risk of bone metastasis (BM) in NSCLC patients at different clinical stages using DLCS. The DL signature successfully predicted BM, with C-indexes of 0.799 and 0.818 for the validation cohorts. DLCS outperformed the DL signature with corresponding C-indexes of 0.806 and 0.834. Ranges for area under the curve at 1, 2, and 3 years were 0.820–0.865 for internal and 0.860–0.884 for external validation cohorts. Furthermore, DLCS successfully stratified patients with different clinical stages of NSCLC as high- and low-risk groups for BM (p
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