Abstract Background State governments in the United States are increasingly viewing marijuana legalization as a policy option for controlling the opioid epidemic under the premise that marijuana is a less harmful substitute for opioids. The purpose of this study is to assess whether marijuana use is associated with decreased odds of prescription opioid use. Methods A cross-sectional study design was applied to toxicological testing data from two national samples of drivers: 1) the 2011–2016 Fatality Analysis Reporting System (FARS) and 2) the 2013–2014 National Roadside Survey of Alcohol and Drug Use by Drivers (NRS). Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) estimated from multivariable logistic regression models were used to assess the associations of marijuana use with prescription opioid use and alcohol use. Results Among the 47,602 drivers from the FARS, 15.7% tested positive for marijuana and 6.9% positive for prescription opioids. Compared with drivers testing negative for marijuana...