Multiple sclerosis (MS) is a chronic inflammatory demyelinating and degenerative disorder of the central nervous system. Accelerated brain volume loss (BVL) has emerged as a promising magnetic resonance imaging marker (MRI) of neurodegeneration, correlating with present and future clinical disability. We have systematically selected MS patients fulfilling ‘no evidence of disease activity-3′ (NEDA-3) criteria under high-efficacy disease-modifying treatment (DMT) from the database of two Belgian MS centers. BVL between both MRI scans demarcating the NEDA-3 period was assessed and compared with a group of prospectively recruited healthy volunteers who were matched for age and gender. Annualized whole brain volume percentage change was similar between 29 MS patients achieving NEDA-3 and 24 healthy controls (−0.25 ± 0.49 versus −0.24 ± 0.20, p = 0.9992; median follow-up 21 versus 33 months; respectively). In contrast, we found a mean BVL increase of 72%, as compared with the former, in a second control group of MS patients (n = 21) whom had been excluded from the NEDA-3 group due to disease activity (p = 0.1371). Our results suggest that neurodegeneration in MS can slow down to the rate of normal aging once inflammatory disease activity has been extinguished and advocate for an early introduction of high-efficacy DMT to reduce the risk of future clinical disability.