Objective: To identify evidence in the literature presenting the economic and humanistic (based on health state utility values [HSUVs]) burden of multiple sclerosis (MS) and report the incremental burden of secondary progressive MS (SPMS) compared with relapsing-remitting MS (RRMS).Methods: Electronic databases (Embase, MEDLINE, MEDLINE In-Process, Cochrane Library) and other relevant repositories were systematically searched from the date of inception until November 2019 for evidence on the economic burden of MS, or HSUVs in patients with MS. Data were extracted from studies investigating cost data or HSUVs for patients with SPMS compared with RRMS.Results: In total, 25 studies were identified that reported data on the economic and HSUV burden of SPMS versus RRMS: 18 studies reported cost data and nine presented HSUVs. Overall, costs associated with SPMS were consistently higher than those for RRMS. Major cost drivers appeared to shift following transition from RRMS to SPMS, with higher direct medical costs associated with RRMS than with SPMS, while the opposite was true for direct non-medical costs and indirect costs. In all studies presenting HSUVs specifically in patients with SPMS, the disease burden was greater (indicated by lower HSUV scores or a negative regression coefficient vs RRMS) for patients with SPMS than for those with RRMS. Fatigue and psychological stress (including depression) were identified as key drivers of this reduced health-related quality of life (HRQoL).Conclusions: Our findings indicate that SPMS is associated with higher costs and more substantial HRQoL decrements than RRMS. These results highlight the substantial unmet need for effective treatments that can slow disease progression in patients with SPMS, which, in turn, would reduce the rate of HRQoL deterioration and increasing healthcare costs.