When compared to the general population, people with multiple sclerosis (MS) had a higher risk of critical illness, sepsis, and sepsis-related death. Sepsis epidemiology and its impact on the outcomes of critically ill MS patients were unknown. A statewide dataset was used to identify ICU admissions in Texas aged more than or equal to 18 years with an MS diagnosis from 2010 to 2017. The study looked at the prevalence of sepsis and its impact on inpatient resource utilization and short-term mortality (a combination of in-hospital death and discharge to hospice). Sepsis was found in 6,244 (31.5%) of the 19,837 ICU admissions with MS. Those with sepsis were older (aged ≥65 years 34.1% vs 24.1%), less frequently racial/ethnic minority (32.6% vs 35.2%), and had a higher mean [SD] Deyo comorbidity index (1.7 [1.8] vs 1.2 [1.7]). Sepsis was associated with a 42.7% longer hospital length of stay and a 26.2% increase in total hospital charges in adjusted analyses. The risk-adjusted short-term mortality rate among ICU admissions with and without sepsis was 13.4% vs. 3.3%, respectively. Sepsis was present in nearly one-third of MS ICU admissions, had a significant negative impact on hospital resource utilization, and was associated with a fourfold increase in short-term mortality.