BackgroundLittle is known about the economic consequences of living with severe multiple sclerosis (SMS). AimsTo assess the cost-effectiveness of a home-based palliative approach (HPA) for people with SMS (pwSMS). To assess direct healthcare costs in this population. MethodsPwSMS from three Italian centers received (2:1 ratio) HPA or usual care over six months. Direct healthcare costs were collected on a monthly basis. Incremental cost-effectiveness was gauged from a national healthcare system (NHS) and a personal perspective, considering the Palliative Outcome Scale-Symptoms-MS (POS-S-MS) and the EuroQol five-dimension descriptive system quality-adjusted life years (EQ-5D-3L QALYs), both completed at baseline, after three and six months. ResultsOf 78 randomized pwSMS, 76 (50 HPA, 26 usual care) were analyzed. Mean QALYs were close to zero, and the mean group difference was -0.006 (95% CI -0.057 to 0.044). The mean baseline-adjusted cost difference was € -394 (95% confidence interval, CI -3,532 to 2,743). POS-S-MS cost-effectiveness showed a slight mean reduction of symptom burden (-1.9; 95% CI -1.1 to 5.0) with unchanged costs. Mean direct costs due to MS were € 23,195/year, almost equally distributed between NHS (€ 13,108) and pwSMS (€ 10,087). Personal care, medications and home rehabilitation accounted for 80% of total expenditures. Most personal care costs were covered by pwSMS, and these costs were 3/4 of pwSMS out-of-pocket. ConclusionsThe slight reduction of symptom burden produced by the HPA was not associated with an increase in costs. NHS and pwSMS almost equally sustained these costs. Trial registrationCurrent Controlled Trials ISRCTN73082124.