BACKGROUND: The Indiana University Center for Global Health coined the term reciprocal innovation to describe bidirectional, mutually beneficial research and translational research within long-term global health partnerships. Inspired by a 30-year global health partnership between Indiana University (Indianapolis, IN, USA) and Moi University College of Health Sciences (Eldoret, Kenya), we developed a reciprocal innovation programme based at the Indiana Clinical and Translational Sciences Institute (Indianapolis, IN, USA). We describe early lessons in building this programme and its potential as a transformative approach to address systemic inequities across high-income and low/middle-income countries. METHODS: The reciprocal innovation programme, established in 2016, aims to identify and support research on the design, testing, replication, and dissemination of health technologies and interventions that have applicability across high-income and low-income and middle-income countries. Central to this process is the building of equitable, mutually beneficial global health partnerships. Programme activities, informed by an environmental scan of stakeholders in Indiana, USA and Kenya, included funding a competitive research grants programme, hosting workshops for community-based and global health researchers, and creating educational and training videos on reciprocal innovation approaches. FINDINGS: To date, the programme has awarded more than 30 grants totalling US$ 610 000 for research in nine countries. Examples of funded cross-continent reciprocal innovation projects include the application of rapid testing for falsified drug detection in Malawi and for use by harm reduction organisations in the USA, and the adoption of a Kenyan community health-worker model to reduce infant mortality in Indiana. These projects, among others, are resulting in measurable improvements in health outcomes in both Indiana and abroad, and continue to expand. Three global reciprocal innovation workshops have been held and an online database has been created to showcase research in this area. INTERPRETATION: In the first 5 years of the programme, we have engaged investigators and launched projects internationally in reciprocal innovation, illustrating a new approach to global health research, translation, and partnerships. Although this programme is in early stages and still developing metrics to assess its success, reciprocal innovation has the potential to help to address systemic inequities and global challenges in both high-income and low-income and middle-income settings through long-term, equitable, and mutually beneficial partnerships. FUNDING: This work is partly supported by the National Center for Advancing Translational Sciences at the National Institutes of Health (Bethesda, MD, USA) grant number UL1TR00252.