The objective of this study was to determine the prevalence of psychoactive drug and alcohol use among general drivers and predictors of the drug use in Thailand. One thousand six hundred and thirty-five motor vehicle drivers were randomly selected from five geographical regions of Thailand between December 2005 and May 2006. The prevalence of psychoactive drugs was determined using urine tests by gas chromatography/mass spectrometry (GC/MS). Among 1635 drivers, 5.5% were tested positive for breath alcohol with 2% having a level exceeding the legal limit (> or =50mg%). Psychoactive drug was presented in 158 (9.7%) urine samples for drug analysis. The top 3 most frequently detected licit drugs were antihistamines (2.0%), sedative cough suppressant (0.7%) and benzodiazepines (0.2%). Illicit drugs detected included amphetamine (1.8%), cannabis (1.1%), mitragynine (Kratom) (0.9%) and morphine (0.1%). Only type of driver (commercial/non-commercial) was a significant predictor with psychoactive drug use. The prevalence of psychoactive drug use among drivers not involved in road crashes in Thailand was not as low as an earlier study in Europe using objective measurements, particularly among commercial drivers. However, for illicit drugs, the prevalence detected in this study was lower than those of earlier studies from high-income countries.