Interoperability of health related information is one of the agendas of many counties in the world, with no exception to Nigeria and other developing countries. This is because healthcare costs are rising exponentially. However, interoperability of health related information seem largely unattainable in Nigeria due to reluctance to change from the traditional paper based healthcare system to the use of e-health systems, inadequate ICT infrastructure, poor utilization of the available ICT resources, erratic power supply, increased burden of underdevelopment, poverty, political instability, shortage of educational capacity in Nigeria rural and urban healthcare centers, low level of ICT awareness, poor maintenance culture as well as corruption. Consequently, the healthcare system in Nigeria is saddled with high cost, high rate of disease outbreak driven by HIV/AIDs, malaria and other infectious diseases which results in a high rate of mortality. Nevertheless, the urgent need to meaningfully exchange safe and reliable health information is a key priority to the healthcare system in Nigeria as the qualities of patients’ care depend majorly on the timely acquisition, processing and retrieval of data related to the patient. Thus, this paper attempts to unravel the factors hindering interoperability in the Nigeria healthcare system and suggests ways of making total interoperability a reality in Nigeria healthcare system as well as other developing countries.