AbstractBackground and PurposeAlthough structural disconnection represents the hallmark of multiple sclerosis (MS) pathophysiology, classification attempts based on structural connectivity have achieved low accuracy levels. Here, we set out to fill this gap, exploring the performance of supervised classifiers on features derived from microstructure informed tractography and selected applying a novel robust approach.MethodsUsing microstructure informed tractography with diffusion MRI data, we created quantitative connectomes of 55 MS patients and 24 healthy controls. We then used a robust approach—based on two classical methods of feature selection— to select relevant features from three network representations (whole connectivity matrices, node strength, and local efficiency). Classification accuracy of the selected features was tested with five different classifiers, while their meaningfulness was tested via correlation with clinical scales. As a comparison, the same classifiers were run on features selected with the standard procedure in network analysis (thresholding).ResultsOur procedure identified 11 features for the whole net, five for local efficiency, and seven for node strength. For all classifiers, the accuracy was in the range 64.5%‐91.1%, with features extracted from the whole net reaching the maximum, and overcoming results obtained with the standard procedure in all cases. Correlations with clinical scales were identified across functional domains, from motor and cognitive abilities to fatigue and depression.ConclusionApplying a robust feature selection procedure to quantitative structural connectomes, we were able to classify MS patients with excellent accuracy, while providing information on the white matter connections and gray matter regions more affected by MS pathology.