To examine long-term trends and demographic disparities in mortality from multiple sclerosis (MS) with sepsis as a contributing cause in the United States from 1999 to 2020.

Sepsis is a serious complication and a common cause of death in people with MS because of their increased risk of infection and long-term disability. However, national trends and differences in MS-related sepsis deaths across populations are not well understood.

A population-based study was conducted using data from the CDC WONDER Multiple Cause of Death database from 1999 to 2020. Deaths with MS as the underlying cause and sepsis as a contributing cause were identified using ICD-10 codes. AAMRs were calculated per 100,000 population. Temporal trends were assessed using Joinpoint regression to estimate annual percent change (APC) with 95% confidence intervals (CIs).

Between 1999 and 2020, the overall AAMR increased from 0.246 (95% CI: 0.222–0.269) in 1999 to 0.319 (95% CI: 0.296–0.342) in 2020 (APC: 0.59%; 95% CI: 0.18%–1.00%; p=0.007). The increase was more pronounced among females (AAMR: 0.284→0.373; APC: 0.76%; p=0.002) than males (0.200→0.257; APC: 0.27%; p=0.44). By race, White individuals showed a significant rise (APC: 0.60%; p=0.009), while Black individuals had higher absolute rates but a non-significant trend. Regionally, mortality rose significantly in the West (APC: 1.13%; p=0.016) and South (APC: 0.84%; p=0.021), with stable trends in the Midwest and Northeast. Nonmetropolitan areas experienced a steeper rise (APC: 1.66%; p=0.001) than metropolitan areas (APC: 0.48%; p=0.032).

Mortality from multiple sclerosis with sepsis as a contributing cause has modestly increased in the United States. The rise was mainly seen among females, White individuals, and residents of the South and West regions. Higher growth in rural areas highlights the need for better infection prevention and sepsis care in patients with multiple sclerosis.