The objective of the study was to determine the prevalence of alcohol, psychoactive medicinal drugs and illegal drugs among drivers in Norwegian road traffic. Drivers of motor vehicles were selected from April 2005 to April 2006 in the south-eastern part of Norway, surrounding, but not including the capital, Oslo. A stratified two-stage cluster sampling procedure was used. In the first stage, random road sites and time intervals were selected, and in the second stage, drivers were stopped by random at those sites and time intervals. Altogether about 12,000 drivers were asked to provide a sample of oral fluid (saliva) and answer a few questions. Samples of oral fluid were obtained from 88% of the drivers, of whom 30% were females and 70% males. The prevalence of each drug was estimated by a weighted average using weights adjusted for under- or over-sampling compared to traffic statistics. Alcohol or drugs were found in oral fluid samples of 4.5% of the drivers; alcohol in 0.4%, psychoactive medicinal drugs in 3.4%, and illegal drugs in 1.0%. Illegal drugs were found more frequently in samples from younger drivers, while psychoactive medicinal drugs were more frequently found in samples from older drivers. Psychoactive medicinal drugs were more prevalent among females than males, among drivers stopped on working days rather than weekends, and among those who reported annual driving distances less than 16,000 km. The drugs found most frequently were zopiclone (1.4%), benzodiazepines (1.4%), codeine (0.8%), tetrahydrocannabinol (0.6%) and amphetamines (0.3%). Two or more drugs were found in 0.6% of the samples, corresponding to 15% of the drug-positive drivers.