Background: In the context of road safety, this study aims to examine the prevalence of drug use in a random sample of drivers. Methods: A stratified probabilistic sample was designed to represent vehicles circulating on non-urban roads. Random drug tests were performed during autumn 2014 on 521 drivers in Catalonia (Spain). Participation was mandatory. The prevalence of drug driving for cannabis, methamphetamines, amphetamines, cocaine, opiates and benzodiazepines was assessed. Results: The overall prevalence of drug use is 16.4% (95% CI: 13.9; 18.9) and affects primarily younger male drivers. Drug use is similarly prevalent during weekdays and on weekends, but increases with the number of occupants. The likelihood of being positive for methamphetamines and cocaine is significantly higher for drivers of vans and lorries. Conclusions: Different patterns of use are detected depending on the drug considered. Preventive drug tests should not only be conducted on weekends and at night-time, and need to be reinforced for drivers of commercial vehicles. Active educational campaigns should focus on the youngest age-group of male drivers.