Conventional brain magnetic resonance imaging (MRI) in systemic diseases with central nervous system involvement (SDCNS) may imitate MRI findings of multiple sclerosis (MS). In order to better describe the MRI characteristics of these conditions, in our study we assessed brain volume parameters in MS (n = 58) and SDCNS (n = 41) patients using two-dimensional linear measurements (2DLMs): bicaudate ratio (BCR), corpus callosum index (CCI) and width of third ventricle (W3V). In SDCNS patients, all 2DLMs were affected by age (CCI = 0.005, BCR < 0.001, W3V < 0.001, respectively), whereas in MS patients only BCR and W3V were ( = 0.001 and = 0.015, respectively). Contrary to SDCNS, in the MS cohort BCR and W3V were associated with T1 lesion volume (T1LV) ( = 0.020, = 0.009, respectively) and T2 lesion volume (T2LV) ( = 0.015, = 0.009, respectively). CCI was associated with T1LV in the MS cohort only ( = 0.015). Moreover, BCR was significantly higher in the SDCNS group ( = 0.01) and CCI was significantly lower in MS patients ( = 0.01). The best predictive model to distinguish MS and SDCNS encompassed gender, BCR and T2LV as the explanatory variables (sensitivity 0.91; specificity 0.68; AUC 0.86). Implementation of 2DLMs in the brain MRI analysis of MS and SDCNS patients allowed for the identification of diverse patterns of local brain atrophy in these clinical conditions.