Sepsis is a life-threatening condition and is one of the leading causes of death in the United States. The burden of sepsis-related mortality in the United States in recent years is not well characterized. We sought to describe sepsis-related mortality rates and mortality trends in the United States from 2005 to 2018.Retrospective population-based study.We used the Multiple Cause of Death Database available through the Centers for Disease Control and Prevention website.Decedents with sepsis-related deaths were identified using previously validated International Classification of Diseases codes.None.From 2005 to 2018, 6.7% of decedents had a diagnosis of sepsis. The overall sepsis-related mortality rates remained stable in both males (57 deaths per 100,000) and females (45.1 deaths per 100,000) during this period. Compared with Whites, the sepsis-related mortality rates were higher in Blacks (rate ratio = 1.78), Native Americans (rate ratio = 1.43), and Hispanics (rate ratio = 1.04) and were lower in Asians (rate ratio = 0.73). Sepsis-related mortality rates declined in Blacks, Hispanics, and Asians but increased in Whites and Native Americans. The majority of sepsis-related deaths occurred in the hospital. The percentage of deaths in the nursing home decreased, whereas deaths occurring at home and hospice increased.From 2005 to 2018, the overall sepsis-related mortality rates were stable, but there were significant racial and gender disparities in mortality trends. Further research is needed to evaluate the genetic and environmental contributors to these differences.