Background Comorbidities are common among people with multiple sclerosis (PwMS); yet, their impact on the cost-of-illness (COI) in MS is unknown. Objective Explore the heterogeneity in COI trajectories among newly diagnosed PwMS in relation to type of comorbidity. Methods A nationwide longitudinal cohort study, using prospectively collected Swedish register data for seven years. The COI/year of 639 PwMS diagnosed in 2006, when aged 25–60, was estimated until 2013. Using healthcare data, PwMS were categorised into six comorbidity groups: ocular; cardiovascular, genitourinary or cancer disease; musculoskeletal; mental; neurological other than MS; and injuries. One group of PwMS without comorbidity was also created. Group-based trajectory modelling was applied, examining different COI trajectories within each comorbidity group. Results Across the seven follow-up years, PwMS with mental comorbidities had the highest COI overall (€36,482). Four COI trajectories were identified within each comorbidity group; the largest trajectory had high healthcare costs and productivity losses (36.3%–59.6% of PwMS, across all comorbidity groups). 59.6% of PwMS with mental comorbidity had high healthcare costs and productivity losses. Conclusion High COI and heterogeneity in COI trajectories could be partly explained by the presence of chronic comorbidities in the year around MS diagnosis, including the presence of mental comorbidity.