The Centers for Disease Control and Preventions (CDC) National Center for Injury Prevention and Control (NCIPC) is soliciting investigator-initiated research to rigorously evaluate and examine effectiveness of strategies, programs, or policies (collectively referred to as strategies) for preventing polysubstance-impaired driving and associated crashes, nonfatal injuries, or deaths. Polysubstance-impaired driving means driving while impaired by two or more substances, such as alcohol and opioids or cannabis and alcohol. Comprehensive evaluations of strategies to prevent polysubstance-impaired driving are lacking and urgently needed given the changing landscape of substance use and impaired driving. Additionally, given inequitable impacts on some populations (American Indian and Alaska Native [AIAN] communities, rural populations, etc.), research is needed to examine strategy effectiveness among different populations. This NOFO supports research that can help fill these gaps. Research may include, but is not limited to, evaluation of the impact of any of the following on preventing polysubstance-impaired driving and related outcomes: 1) Evidence-based alcohol-impaired driving strategies that may also prevent polysubstance-impaired driving. Examples include, but are not limited to, screening and brief intervention and alternative transportation or transit programs. 2) Strategies that prevent excessive alcohol use, harmful substance use, or substance use disorders that have the capacity to also prevent polysubstance-impaired driving. Examples include, but are not limited to, taxation or pricing policies for alcohol and cannabis, social norming campaigns, and multi-component coalition-based strategies (e.g., Drug Free Communities Programs or similar efforts). This NOFO encourages examination of strategy effects on polysubstance-impaired driving and associated injuries and deaths among the overall population and disproportionately affected populations.