Background: Multiple sclerosis (MS) and cerebral small vessel disease (CSVD) are relatively common radiological entities that occasionally necessitate differential diagnosis. Purpose: To investigate the differences in magnetic resonance imaging (MRI) signal intensity (SI) between MS and CSVD related white matter lesions. Material and Methods: On 1.5-T and 3-T MRI scanners, 50 patients with MS (380 lesions) and 50 patients with CSVD (395 lesions) were retrospectively evaluated. Visual inspection was used to conduct qualitative analysis on diffusion-weighted imaging (DWI)_b1000 to determine relative signal intensity. The thalamus served as the reference for quantitative analysis based on SI ratio (SIR). The statistical analysis utilized univariable and multivariable methods. There were analyses of patient and lesion datasets. On a dataset restricted by age (30–50 years), additional evaluations, including unsupervised fuzzy c-means clustering, were performed. Results: Using both quantitative and qualitative features, the optimal model achieved a 100% accuracy, sensitivity, and specificity with an area under the curve (AUC) of 1 in patient-wise analysis. With an AUC of 0.984, the best model achieved a 94% accuracy, sensitivity, and specificity when using only quantitative features. The model's accuracy, sensitivity, and specificity were 91.9%, 84.6%, and 95.8%, respectively, when using the age-restricted dataset. Independent predictors were T2_SIR_max (optimal cutoff=2.1) and DWI_b1000_SIR_mean (optimal cutoff=1.1). Clustering also performed well with an accuracy, sensitivity, and specificity of 86.5%, 70.6%, and 100%, respectively, in the age-restricted dataset. Conclusion: SI characteristics derived from DWI_b1000 and T2-weighted-based MRI demonstrate excellent performance in differentiating white matter lesions caused by MS and CSVD. [ABSTRACT FROM AUTHOR]