Byrne AB, et al. - In view of a dramatic increase in flavivirus infections in the last decades in tropical and subtropical regions of the world and the reports inscribing pathogenic as well as protective effects of complement in flavivirus infections, researchers performed this review with the aim to provide a comprehensive and updated overview of the role of the complement system in flavivirus infections, with special focus on antibody-dependent enhancement (ADE) of flavivirus infections. Despite that diseases of great public health concern are caused by flavivirus infections, there are no antivirals, specific treatments or vaccines for most of them. This review suggested antiviral effects of complement and its regulation, as well as mechanisms of complement evasion and dysregulation of complement activity during viral infection leading to pathogenesis. Insights into the classical pathway activation and its protective role on antibody-dependent enhancement of flavivirus infections are particularly featured in this review. ADE is identified to be a major barrier to dengue vaccine development and is a relevant consideration for ZIKV vaccination in dengue endemic regions. Determination of how to decrease ADE by interactions with C1q or other complement factors may aid in developing safe vaccine approaches and therapeutic strategies.