Objectives. To assess cannabis and alcohol involvement among motor vehicle crash (MVC) fatalities in the United States. Methods. In this repeated cross-sectional analysis, we used data from the Fatality Analysis Reporting System from 2000 to 2018. Fatalities were cannabis-involved if an involved driver tested positive for a cannabinoid and alcohol-involved based on the highest blood alcohol concentration (BAC) of an involved driver. Multinomial mixed-effects logistic regression models assessed cannabis as a risk factor for alcohol by BAC level. Results. While trends in fatalities involving alcohol have remained stable, the percentage of fatalities involving cannabis and cannabis and alcohol increased from 9.0% in 2000 to 21.5% in 2018, and 4.8% in 2000 to 10.3% in 2018, respectively. In adjusted analyses, fatalities involving cannabis had 1.56 (95% confidence interval [CI] = 1.48, 1.65), 1.62 (95% CI = 1.52, 1.72), and 1.46 (95% CI = 1.42, 1.50) times the odds of involving BACs of 0.01% to 0.049%, 0.05% to 0.079%, and 0.08% or higher, respectively. Conclusions. The percentage of fatalities involving cannabis and coinvolving cannabis and alcohol doubled from 2000 to 2018, and cannabis was associated with alcohol coinvolvement. Further research is warranted to understand cannabis- and alcohol-involved MVC fatalities. (Am J Public Health. Published online ahead of print October 28, 2021:e1–e10. https://doi.org/10.2105/AJPH.2021.306466 )