BackgroundThis study examined racial/ethnic and educational disparities in US synthetic opioid overdose mortality East and West of the Mississippi River. MethodsUsing restricted-access 2018–2021 mortality data from the Centers for Disease Control and Prevention and population estimates from the American Community Survey, age-standardized rate ratios (SRRs) and 95% Confidence Intervals (CIs) were used to compare rates of synthetic opioid mortality by race/ethnicity and educational attainment level in the regions East and West of the Mississippi River. ResultsRacial/ethnic disparities in synthetic opioid mortality rates, relative to the Non-Hispanic (NH) White population, were observed in the NH Black (SRR, 1.5 [95% CI, 1.5–1.6]) and NH American Indian/Alaska Native (SRR, 2.1 [95% CI, 1.9–2.2]) populations in the West, and the Puerto Rican (SRR, 1.3 [95% CI, 1.3–1.3]) and NH American Indian/Alaska Native (SRR, 1.5 [95% CI, 1.4–1.6]) populations in the East. Relative to those with a Bachelor’s degree or higher: in the West, the synthetic opioid mortality rate was more than seven times as high for those with a high school diploma only (SRR 7.7 [95% CI, 7.4–8.0]), and in the East, approximately thirteen times as high for those with a high school diploma only (SRR, 13.0 [95% CI, 12.7–13.3]) or less than a high school diploma (SRR, 13.3 [95% CI, 13.0–13.7]). ConclusionDisparities in rates of synthetic opioid mortality differ in the eastern and western US, supporting tailored responses within each region.