Multiple sclerosis (MS) is an autoimmune disease of unknown aetiology affecting the central nervous system [1], [2]. In most patients, the disease course is characterised by repeated relapses associated with disease progression [3]. Traditionally, in relapsing MS, the accrual of irreversible disability has been attributed to incomplete recovery from relapse, whereas relapse-independent mechanisms are considered the hallmark of the progressive forms of the disease [4], [5]. However, accumulating evidence suggests that progression unrelated to relapses is not restricted to patients diagnosed with the progressive forms of MS. In the earliest phases of MS and in patients classified as having a typical relapsing-remitting disease, a substantial proportion of disability accumulation occurs independent of relapse activity. Despite the lack of concomitant clinically evident relapses, clinical deterioration has been termed progression independent of relapse activity (PIRA) or silent progression, in contrast to relapse-associated disability worsening (RAW) [5], [6], [7], [8], [9], [10]. Recently, a systematic review reported that in the context of the variable definitions of PIRA, along with other methodological differences related to disease modifying therapy (DMT) use and follow-up duration, the reported proportion of MS patients experiencing PIRA varied from 4% to 24% [11]. However, few studies have investigated the neural substrates of the PIRA in relapse-free relapse remitting MS (RRMS) or secondary progressive MS (SPMS). Moreover, it has not been fully elucidated how the regional brain atrophy silently (i.e,. without relapse) progressed over the course of MS, with or without disability progression. Therefore, this retrospective 2-year follow-up study evaluated and compared the longitudinal relapse-free brain segmental atrophy rate in specific brain regions of patients with RRMS and SPMS.