Objective To explore the potential of a post-processing technique combining FLAIR and T 2 * (FLAIR*) to distinguish between lesions caused by multiple sclerosis (MS) from cerebral small vessel disease (SVD) in a clinical setting. Methods FLAIR and T 2 * head datasets acquired at 3T of 25 people with relapsing MS (pwRMS) and ten with pwSVD were used. After post-processing, FLAIR* maps were used to determine the proportion of white matter lesions (WML) showing the ‘vein in lesion’ sign (VIL), a characteristic histopathological feature of MS plaques. Sensitivity and specificity of MS diagnosis were examined on the basis of >45% VIL + and >60% VIL + WML, and compared with current dissemination in space (DIS) MRI criteria. Results All pwRMS had >45% VIL + WML (range 58–100%) whilst in pwSVD the proportion of VIL + WML was significantly lower (0–64%; mean 32±20%). Sensitivity based on >45% VIL + was 100% and specificity 80% whilst with >60% VIL + as the criterion, sensitivity was 96% and specificity 90%. DIS criteria had 96% sensitivity and 40% specificity. Conclusion FLAIR* enables VIL + WML detection in a clinical setting, facilitating differentiation of MS from SVD based on brain MRI. Key points • FLAIR* in a clinical setting allows visualization of veins in white matter lesions. • Significant proportions of MS lesions demonstrate a vein in lesion on MRI. • Microangiopathic lesions demonstrate a lower proportion of intralesional veins than MS lesions. • Intralesional vein-based criteria may complement current MRI criteria for MS diagnosis.