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Background Differentiating between malignant and benign solitary pulmonary lesions (SPLs) is challenging. Purpose To determine diagnostic performance of intravoxel incoherent motion-based diffusion-weighted imaging (DW-IVIM) in distinguishing malignant from benign SPLs, using histogram analysis derived whole-tumor and single-section region of interest (ROI). Material and Methods This retrospective study received institutional review board approval. A total of 129 patients with diagnosed SPLs underwent DW-IVIM and apparent diffusion coefficient (ADC). ADC, slow diffusion coefficient (D), fast diffusion coefficient (D*), and perfusion fraction (f) were calculated separately by outlining whole-tumor and single-section ROI. Inter-observer reliability was assessed by inter-class correlation coefficient (ICC). ADC and DW-IVIM parameters were analyzed using independent-sample T-test. Receiver operating characteristic (ROC) analysis was constructed to determine diagnostic performance. Multiple logistic regression was performed to identify independent factors associated with malignant SPLs. Results There were 48 benign SPLs found in 35 patients and 94 patients with lung cancer (LC). ICC for whole-tumor ROI (range, 0.89-0.95) was higher than that for single-section ROI (range, 0.61-0.71). Mean ADC and D were significantly lower in the malignant group. ADC and D 10th showed significantly higher AUC values than did mean ADC and D. D showed significantly higher diagnostic accuracy in mean, 10th, and 25th percentiles than ADC values (all Ps < 0.05). D 10th was found to be an independent factor in discriminating LCs with an odds ratio of -1.217. Conclusion Volumetric analysis had higher reproducibility and diagnostic accuracy than did single-section. Further, compared to ADC, D value differentiated benign SPLs from LCs more accurately. [ABSTRACT FROM AUTHOR]