After seven years of implementation, the National Health Insurance Scheme (NHIS) has achieved varying levels of enrolment coverage within the 10 regions of Ghana with different rural-urban populations. Implementation problems and low coverage challenges threaten the long term sustainability of the scheme. Using a sample of 4,214 individuals who are 18 years and above from the COHEiSION Project baseline survey and employing bivariate and logistic regression analyses, separate estimations are performed for the pooled sample and the Greater Accra and Western region sub-samples to determine the rural-urban differences in the determinants of demand for health insurance in these two regions in Ghana. We found statistically significant differences in the demographic and socio-economic characteristics of rural and urban adults for the pooled sample and within the two regions. Overall, rural adults were more likely than urban adults to enroll in health insurance. However, when the regions were analyzed separately, the results were conflicting. Whilst in the Greater Accra region rural adults are more likely than urban adults to enroll in health insurance, in the western region we found the opposite; urban adults are more likely than rural adults to enroll. Sex, educational attainment, employment status and health status were better and stronger predictors of health insurance enrolment than rural-urban locality of residence. We recommend that future studies on determinants of enrolment in health insurance and policy makers should focus on regional or district level differences to adequately capture the different demographic and socio-economic factors that might be responsible for the observed differences in enrollment coverages and find region and district specific interventions to address them.