Driving under the influence of alcohol and/or psychoactive substances increases the risk of severe, even fatal motor vehicle accidents. The aim of this descriptive study was to present the impact of alcohol and/or psychoactive substances on fatal road traffic accidents (RTAs) during the period 2011-2017. For this purpose, the toxicological investigation reports from the Department of Forensic Medicine and Toxicology of the University of Athens were used. In total, 1,841 (32.2%) of the autopsies conducted by the Department of Forensic Medicine and Toxicology of the National and Kapodistrian University of Athens over a 7-year period (2011-2017) were victims of fatal RTAs. Blood and urine samples were collected and analyzed for the presence of alcohol and psychoactive substances. The results were classified according to sex, age, victim (car driver, motorcyclist, pedestrian, or passenger) and the date the accident occurred (day, month and year). In total, 40.7% of the RTA-related fatalities were associated with alcohol consumption, among which 20.3% were car drivers. Of these, 87.3% were male victims. A higher frequency of RTA-related fatalities associated with a blood alcohol concentration (BAC) >110 mg/dl was encountered in younger compared with older age groups. Psychoactive substances were detected in 348 (18.9%) of the victims (cannabis in 46.6% of these, benzodiazepines in 25.9%, opiates in 16.4% and cocaine in 11.1% of these). The percentage of the RTA-related victims that had consumed alcohol in combination with other psychoactive substances was 4.5%. On the whole, the findings of this study suggest that alcohol and psychoactive substances are probably risk factors for RTA-related fatalities.