A multi-center case-control study was conducted on 3398 fatally-injured drivers to assess the effect of alcohol and drug use on the likelihood of them being culpable. Crashes investigated were from three Australian states (Victoria, New South Wales and Western Australia). The control group of drug- and alcohol-free drivers comprised 50.1% of the study population. A previously validated method of responsibility analysis was used to classify drivers as either culpable or non-culpable. Cases in which the driver "contributed" to the crash (n=188) were excluded. Logistic regression was used to examine the association of key attributes such as age, gender, type of crash and drug use on the likelihood of culpability. Drivers positive to psychotropic drugs were significantly more likely to be culpable than drug-free drivers. Drivers with Delta(9)-tetrahydrocannabinol (THC) in their blood had a significantly higher likelihood of being culpable than drug-free drivers (odds ratio (OR) 2.7, 95% CI 1.02-7.0). For drivers with blood THC concentrations of 5 ng/ml or higher the odds ratio was greater and more statistically significant (OR 6.6, 95% CI 1.5-28.0). The estimated odds ratio is greater than that for drivers with a blood alcohol concentration (BAC) of 0.10-0.15% (OR 3.7, 95% CI 1.5-9.1). A significantly stronger positive association with culpability was seen with drivers positive to THC and with BAC > or =0.05% compared with BAC > or =0.05 alone (OR 2.9, 95% CI 1.1-7.7). Strong associations were also seen for stimulants, particularly in truck drivers. There were non-significant, weakly positive associations of opiates and benzodiazepines with culpability. Drivers positive to any psychoactive drug were significantly more likely to be culpable (OR 1.8, 95% CI 1.3-2.4). Gender differences were not significant, but differences were apparent with age. Drivers showing the highest culpability rates were in the under 25 and over 65 age groups.