Objective: The paper attempts to understand the medical security and disease burden of phenylketonuria (PKU) in Foshan City, and to explore the specific path to establish a multi-level medical security system of PKU in Foshan City. Methods: Based on policy literature research, questionnaire investigation, interviews, data collection and comparative analysis, we summarize relevant experience at home and abroad to comprehensively understand the guarantee level of PKU in Foshan City, and to simulate and predict the affordability of medical insurance fund after improving the guarantee level of patients with PKU. Results: The disease burden of patients with PKU is still heavy in Foshan City, and the accessibility of Food for Special Medical Purpose (FSMP) is still low. Improving the guarantee level of FSMP has a significant impact on the Special Fund for Neonatal Screening of Foshan Women and Children Hospital, which is the main source of security, and the sustainability of security is insufficient. The supplementary medical insurance fund will be able to support the inclusion of FSMP into the scope of inclusive commercial supplementary medical insurance. The basic medical insurance fund can be affordable to include PKU into the scope of Outpatient Special Diseases. Conclusion: A multi-level security system for PKU can be established by including FSMP into the coverage of inclusive commercial supplementary medical insurance, including PKU into the management of Outpatient Special Diseases guaranteed by basic medical insurance, appropriately extending the conditions for the identification of medical assistance for PKU, strengthening multi-sector cooperation, giving full play to the role of charitable donations and social assistance and security, establishing a multi-level security system for PKU and improving the security level of PKU patients in Foshan.