Abstract Background Health literacy difficulties among (groups of) individuals represent a significant public health challenge. Improving health literacy responsiveness of systems and services could reduce health inequalities in communities and patient populations. Methods We conducted a mixed-methods study to improve health literacy responsiveness in three Dutch rheumatology centres, using the OPtimising HEalth LIteracy and Access (Ophelia) approach. Patients and health professionals were involved in an inclusive needs assessment (n = 895 and 39, respectively) and co-design consultations to identify local solutions (n = 14 and 38, respectively). Based on all steps, we formulated transferable lessons learned (outcome-related or process-related) for public health and health care. Results Outcome-related lessons: a mixed-methods Ophelia approach was successful in identifying health literacy challenges and 175 potential solutions. Challenges are similar between disease groups and centres, but require solutions specific to the local context. Recognising challenges at the point of care is difficult. For a healthcare service to be responsive to health literacy needs, increased awareness alone is not enough; it will require a conscious actions and systemic change at multiple levels, including training. Process-related lessons: prerequisites for a successful health literacy responsiveness project include using multidimensional measurements, an inclusive participatory approach with all stakeholders, collaboration with experts in a community of practice, and strong project governance. Conclusions The Ophelia project in rheumatology care was successful in its aims of finding solutions to improve health literacy responsiveness. Public health and healthcare organisations should consider improving their health literacy responsiveness using a grassroots co-design approach. However, project success will depend on the quality of its governance; future programmes should follow a systematic approach. Key messages • Using a ...