Background <p>Multiple sclerosis (MS) subtypes—relapsing–remitting (RRMS), secondary-progressive (SPMS), and primary-progressive (PPMS) – have been associated with distinct cognitive impairment profiles, with progressive subtypes, in contrast to RRMS, showing additional deficits in more widespread domains. Research has largely focused on RRMS, leaving SPMS and PPMS underexplored due to their lower prevalence and limited therapeutic targeting. Data on the interplay between cognitive impairment, mood, and fatigue over time are also scarce. This study examined cognition, fatigue, and psychopathology over a period of one year to identify subtype-specific impairments and progression trajectories.</p> Methods <p>Sixty-six MS patients (22 each with RRMS, SPMS, and PPMS) and 22 healthy controls (HC) were assessed using neuropsychological tests for attention, memory, processing speed, working memory, fluency and visuospatial functions. Patient-reported outcomes for depression, anxiety, and fatigue were also collected. Analyses included correlations, within-group comparisons (paired t-tests), and between-group comparisons (ANOVAs/ANCOVAs).</p> Results <p>Progressive MS subtypes exhibited more severe cognitive impairments, fatigue, and mood disturbances than RRMS. Over one year, treated RRMS patients improved in various cognitive domains, while PPMS patients showed gains only in visuospatial abilities. On the other hand, SPMS patients exhibited no significant changes, suggesting more pronounced cognitive deficits.</p> Conclusions <p>Cognitive impairments differed significantly across MS subtypes. While RRMS patients improved over one year and PPMS patients showed selective gains in one domain, SPMS showed no significant changes, indicating reduced cognitive reserve. These between-group differences suggest different cognitive trajectories. The findings underscore the need for tailored, holistic interventions for different MS subtypes.</p>