The PEPFAR HIV/AIDS program has had noticeable impacts on the Nigerian health system. The impacts are presented using the World Health Organization (WHO) health system six building blocks. These include service delivery, health workforce, health information, medical products, vaccines and technologies, financing and governance. PEPFAR HIV/AIDS program has improved the delivery of prevention and care services for people living with HIV/AIDS (PLWHA). The most important measure of PEPFAR's success is the availability of free ART in Nigeria for PLWHA who need this. The PEPFAR program has brought about increased political awareness of and raised the priority given to public health by governments and civil society through its scaling up response to HIV/AIDS. The scaled-up program has direct benefits on the health workforce by preserving HIV-infected health personnel's lives so that they can live longer enjoy a better quality of life and return to their jobs; all of which invariably enhances the country's health workforce. Moreover, the training and retraining in PEPFAR HIV/AIDS program have boosted both the morale and the skills of the health workforce. Considerable resources have been brought into Nigeria for scaled-up HIV/AIDS treatment by PEPFAR. However, this has contributed to the development of donor dependency syndrome by Nigerian government. There is a non-alignment between PEPFAR HIV/AIDS program and the recipient country's health system. Attention to maternal mortality and other reproductive health services has suffered as non-governmental organizations (NGOs) pursue AIDS money and local governments receive signals from the political center to prioritize HIV/AIDS over other problems that are just as serious. A functional health system is important in prevention of the HIV epidemic. Hence efforts should be made to strengthen health systems. The PEPFAR HIV/AIDS program should be harmonized with the country's health system for maximum impact.