Background: Multiple sclerosis (MS) carries high morbidity and shortens life span. While there is recent recognition of other US minority populations such as blacks and Hispanics being affected with MS, examination of MS-specific mortality trends by race/ethnicity has been lacking. Objective: To investigate MS mortality rates and trends in the United States by sex, age, and race/ethnicity. Methods: We used the Compressed Mortality data file for 1999–2015 in the Wide-ranging online Data for Epidemiological Research system developed by the Center for Disease Control and Prevention to calculate the age-adjusted (US 2000 standard population) and age-specific MS mortality rate (per 100,000) by race/ethnicity and sex over time. Five mutually exclusive racial/ethnic groups were included in the analysis: non-Hispanic (NH) white, NH black, NH Asian or Pacific Islander (API), NH American Indian or Alaska Native, and Hispanic. Results: The average annual age-adjusted MS mortality rate was highest among NH whites (0.90 for males and 1.50 for females) immediately followed by NH blacks (0.75 for males and 1.42 for females), and lowest among APIs (0.05 for males and 0.12 for females). Statistically significant, increasing trend in age-adjusted MS mortality was observed during 1999–2015 among NH whites and NH blacks regardless of sex, more substantially in the latter. Age-specific MS mortality patterns showed NH blacks had the highest rate under age 55 and NH whites had the highest rate after that age point. For these 2 groups, MS mortality increased with age in both sexes and peaked at ages 55–64 for NH blacks and 65–74 for NH whites before declining substantially, while for Hispanic and API groups the risk plateaued after age 55. Conclusion: MS-specific mortality trends demonstrate distinctive differences by race/ethnicity and age. The observations that whites and females are more likely to die from MS is in line with the overall understanding that these groups are affected more by MS. However, the findings of blacks dying at an earlier age and having more substantially increasing mortality trends than whites suggest that MS burden weighs unequally by race. Further investigation into these trends may provide additional evidence into risk or protective factors within each group.