The National Institutes of Health (NIH), through the National Institute of Neurological Disorders and Stroke (NINDS), is soliciting applications for prospective observational comparative effectiveness research (CER) targeting clinical neuroscience. This funding opportunity, structured as a UG3/UH3 cooperative agreement, supports studies on interventions and strategies that evaluate outcomes in real-world settings. The UG3 phase will last up to two years for planning, while the UH3 phase allows an additional five years for implementation, with a strong emphasis on pragmatic study designs that address significant health disparities and under-researched conditions. Key dates include a new opening date of June 19, 2022, and an expiration date of May 8, 2025. The funding mechanism does not support traditional randomized clinical trials but encourages innovative observational studies. Eligible applicants span higher education institutions, nonprofits, and government entities, with a particular interest in projects including diverse patient populations. Applications must demonstrate comprehensive planning, engagement with patient groups, and compliance with all applicable regulations. Review criteria will assess the significance, innovation, approach, and investigator qualifications of submitted proposals, ensuring compliance with NIH standards and methodologies for CER. The NIH’s primary goal is to foster impactful research that informs clinical practices and enhances understanding of neurological disorders in diverse patient populations.