Abstract The Long Life Family Study (LLFS) is a family-based cohort of unusually healthy individuals that has whole genome sequencing (WGS) data on a majority of its participants and is currently generating large scale -omics data on its participants that includes transcriptomics, whole genome bisulfite sequencing, metabolomics and proteomics. Though LLFS does not return any incidental genetic results to study participants currently, LLFS has modified it’s consent form to ask participants whether they would like to receive incidental genetic findings in the future. The availability of WGS data in almost 4000 LLFS participants along with informed consent for return of medically actionable incidental genetic results, ideally positions LLFS to address bioethical issues related to return of genetic results in family-based cohorts. Pharmacogenetics (PGx), the study of the role of genetic variation in drug response phenotypes, is an area within genomic science that can positively impact patient management and consensus guidelines regarding specific genes and variants to be tested are now available. Thus, return of targeted PGx results that are clinically impactful and are supported by several national and international societies represent an opportunity that can be used to develop the bioethical framework for return of incidental genetic results in LLFS. We propose a pilot study at a single US field center (University of Pittsburgh) to demonstrate the feasibility and acceptability of returning limited PGx results from three genes to 200 LLFS participants. We propose to identify ten medically actionable PGx variants in three genes (CYP2C9, CYP2C19 and VKORC1) from WGS data already available in LLFS. We will confirm the observed variants in a CLIA certified laboratory, create a report summarizing the variants identified and the medications impacted by these variants and establish a study specific PGx consultation service to discuss study results with LLFS participants as needed. We propose to ascertain participant-assessed comprehension, decision making, and satisfaction with return of PGx results (Aim 1) at two time-points, immediately and three months after returning PGx results. In addition, we will leverage the family-based structure of the LLFS cohort to evaluate whether the index participants share their PGx results with their family members and ascertain the comprehension, decision making and satisfaction among family members with return of PGx results to the index study participant using a single telephone survey conducted 3 months after returning PGx results (Aim 2). Finally, we will also assess a pharmacist/physician determined impact of the PGx results on medications the LLFS participants to identify any gaps between pharmacist-assessed and participant-assessed impact of PGx results (Aim 2). At the end of this project, we will have addressed important ethical issues surrounding the return of incidental PGx results to research participants and ...