This study aims to contribute to the development of community-responsive research approaches by describing the research methods used in the RxHL study and the interprofessional and community-based collaboration that produced them. The mixed-method RxHL study was developed in close consultation with staff and providers at our research site, a federally qualified health center in Springfield, MA. We utilized quantitative methods including chart review, manual pill counts and self-report surveys to assess factors associated with medication adherence in a diverse population of low-income patients with chronic disease. We triangulated these results with findings from qualitative methods that included in-depth interviews, home visits and chronic disease diaries. We used the constant comparison method and interdisciplinary, participatory team meetings to integrate quantitative and qualitative findings. A community-responsive approach facilitated the recruitment and retention of a diverse sample of patients. Self-report surveys revealed the widespread scope of barriers to care such as medication costs and transportation, and limited health literacy among diverse groups. Qualitative research methods offered a deeper understanding of the social and environmental contexts in which medication adherence takes place. Prioritizing the needs of community partners and research participants facilitates rigorous data collection in clinical settings with maximum participation from community partners.