Polyphosphate, synthesized by all cells, is a linear polymer of inorganic phosphate. When released into the circulation, it exerts prothrombotic and pro-inflammatory activities by modulating steps in the coagulation cascade. We examined the role of polyphosphate in regulating the evolutionarily-related, proteolytic cascade, complement. In erythrocyte lysis assays, polyphosphate comprising >1000 phosphate units, suppressed total hemolytic activity with an IC50 (concentration to reduce maximal lysis to 50%) that was 10-fold lower than with monophosphate. In the ion- and enzyme-independent terminal pathway complement assay, polyphosphate suppressed complement in a concentration- and size-dependent manner. Phosphatase-treated polyphosphate lost its ability to suppress complement, confirming that polymer integrity is required. Sequential addition of polyphosphate to the terminal pathway assay showed that polyphosphate interferes with complement only when added prior to formation of the C5b-7 complex. Physico-chemical analyses using native gels, gel filtration, and differential scanning fluorimetry, revealed that polyphosphate binds to and destabilizes C5b,6, thereby reducing the capacity of the membrane attack complex to bind to and lyse the target cell. In summary, we have added another function to polyphosphate in blood, demonstrating that it dampens the innate immune response by suppressing complement. The findings further establish the complex relationship between coagulation and innate immunity.