Abstract Introduction Commercial motor vehicle (CMV) drivers, particularly drivers of large trucks continue to be a population of concern regarding traffic safety despite the reduction in large truck crash rates over the past decade. Medication and drug use while driving is one important risk factor for large truck crashes. Work-related exposures, such as vibration, manual handling and poor ergonomics contribute to an increased risk for injuries and chronic conditions and are common reasons for opioid analgesic (OA) use by CMV truck drivers. The objectives of this study were to examine the role of OA use in CMV truck drivers involved in fatal crashes by: (a) generating prevalence estimates of OA use; (b) documenting the relationship between OA use and crash responsibility. Methods Case-control study using logistic regression to compare Fatality Analysis Reporting System (1993–2008) record of one or more crash-related unsafe driver actions (UDAs – a proxy measure of responsibility) between drivers with a positive drug test and drivers with a negative drug test for OA, controlling for age, other drug use, and driving history. Results The annual prevalence of OA use among all CMV drivers of large trucks involved in fatal crashes did not exceed 0.46% for any year in the study period and mostly ranged between 0.1 and 0.2%. Male truck drivers using OA had greater odds of committing an UDA (OR: 2.80; 95% CI: 1.64; 4.81). Middle-aged users had greater odds than younger or older users. Conclusion The results of our study indicate that the presence of OAs is associated with greater odds of committing an UDA. This association may have implications for the commercial transport industry and traffic safety. However, the limited prevalence of OA use is encouraging and further research is needed to address the limitations of the study.