Inclusion of uninsured and underinsured (UUI) individuals in clinical research (CR) is necessary to ensure data quality, diversity, generalizability and fairness. Yet, in the USA, UUI persons tend to be excluded from CR. We conducted an ethical analysis of: the regulatory and ethics literature related to protections of, and duty to care for, research participants from vulnerable groups; the nature and scope of the ancillary health care obligations of researchers, and the applicable laws, regulations and practices concerning the care for UUI participants. We consider six examples illustrating the challenges of including UUI persons in CR. We note that addressing fully the challenges of UUI participation in CR requires comprehensive legal and health care reforms. We maintain that even in the absence of such reforms, researchers, study sponsors and Institutional Review Boards can and ought to adopt an inclusive approach to the recruitment of UUI individuals to improve data quality, diversity, generalizability and social justice. We propose such a systematic, proactive and ethically sound approach. It considers the medical and ancillary care needs of UUI participants, addresses them in the study protocol and budget, and includes referral to community health resources, follow-up support, and noting assistance in the research records.