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Background: Despite universal population coverage and equity being a stated policy goal of its NHIS, over a decade since passage of the first law in 2003, Ghana continues to struggle with how to attain it. The predominantly (about 70 %) tax funded NHIS currently has active enrolment hovering around 40 % of the population. This study explored in-depth enablers and barriers to enrolment in the NHIS to provide lessons and insights for Ghana and other low and middle income countries (LMIC) into attaining the goal of universality in Universal Health Coverage (UHC). Methods: We conducted a cross sectional mixed methods study of an urban and a rural district in one region of Southern Ghana. Data came from document review, analysis of routine data on enrolment, key informant in-depth interviews with local government, regional and district insurance scheme and provider staff and community member in-depth interviews and focus group discussions. Results: Population coverage in the NHIS in the study districts was not growing towards near universal because of failure of many of those who had ever enrolled to regularly renew annually as required by the NHIS policy. Factors facilitating and enabling enrolment were driven by the design details of the scheme that emanate from national level policy and program formulation, frontline purchaser and provider staff implementation arrangements and contextual factors. The factors inter-related and worked together to affect client experience of the scheme, which were not always the same as the declared policy intent. This then also affected the decision to enrol and stay enrolled. Conclusions: UHC policy and program design needs to be such that enrolment is effectively compulsory in practice. It also requires careful attention and responsiveness to actual and potential subscriber, purchaser and provider (stakeholder) incentives and related behaviour generated at implementation levels. [ABSTRACT FROM AUTHOR]