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To characterize drug prevalence among fatally injured drivers, identify significant associations (i.e. day of week, time of day, age, gender), and compare findings with those for alcohol.Descriptive and logistic mixed-model regression analyses of Fatality Analysis Reporting System data.US states with drug test results for >80% of fatally injured drivers, 1998–2010.Drivers killed in single-vehicle crashes on public roads who died at the scene of the crash (n = 16 942).Drug test results, blood alcohol concentration (BAC), gender, age and day and time of crash.Overall, 45.1% of fatally injured drivers tested positive for alcohol (39.9% BAC ≥ 0.08) and 25.9% for drugs. The most common drugs present were stimulants (7.2%) and cannabinols (7.1%), followed by ‘other’ drugs (4.1%), multiple drugs (4.1%), narcotics (2.1%) and depressants (1.5%). Drug-involved crashes occurred with relative uniformity throughout the day while alcohol-involved crashes were more common at night (P < 0.01). The odds of testing positive for drugs varied depending upon drug class, driver characteristics, time of day and the presence of alcohol.Fatal single-vehicle crashes involving drugs are less common than those involving alcohol and the characteristics of drug-involved crashes differ, depending upon drug class and whether alcohol is present. Concerns about drug-impaired driving should not detract from the current law enforcement focus on alcohol-impaired driving.