There is an urgent need of fast and accurate methods for the longitudinal quantification of cervical cord atrophy in multiple sclerosis (MS). Aim of this study was to compare a new semi-automatic method [the active surface (AS) method] with an existing cord segmentation method (the Losseff method) to measure cervical cord atrophy progression in MS patients. Using the AS and Losseff methods, normalized cervical cord cross-sectional area (CSA) was compared between 35 MS patients and 9 healthy controls (HC) at baseline and after 2.3 years of follow-up. Correlations with clinical/conventional MRI variables and a power calculation study were also performed. At follow-up, the Losseff method detected a 1 % CSA increase in HC and a 3.5 % decrease in MS patients (p = 0.01), while the AS method detected a 0.1 % decrease in HC and 3 % decrease in MS patients (p = 0.02). The AS method was more sensitive to associations with disability/conventional MRI variables and also provided lower numbers of subjects per arm compared to the Losseff method in a putative clinical trial scenario. Cord AS CSA measurements were more sensitive to longitudinal changes in MS patients than Losseff measurements. Cord AS CSA might be a valuable surrogate outcome measure for monitoring neuroprotection in MS.