The complement system is a central player of the innate immune system. Activation of the complement system protects the host against pathogens. However, uncontrolled synthesis can be detrimental to host. This concise review summarizes the current understanding of the mechanism(s) of complement activation, the mechanism of C3 regulation, and the role of complement in human immunodeficiency virus (HIV) pathogenesis with emphasis on the cross-talk between HIV and complement system in NeuroAIDS and HIV-associated nephropathy (HIVAN).