In the last decades evidence was obtained that protein S not only acts as cofactor of activated protein C (APC) in the downregulation of coagulation, but also expresses anticoagulant activity in the absence of APC. The search for the mechanism(s) underlying the APC-independent anticoagulant activity of protein S was hampered by the fact that protein S exhibited 2 seemingly identical anticoagulant activities in model systems and in plasma. Later it was shown that the anticoagulant activity of purified protein S in model systems was dependent on the concentration of phospholipid vesicles and was explained by low amounts of protein S multimers generated during purification that effectively inhibited phospholipid-dependent coagulation reactions via competition for phospholipid binding sites. Plasma does not contain multimers, and the anticoagulant activity of protein S in plasma was not affected by the phospholipid concentration but was dependent on the amount of tissue factor (TF) used for initiation of thrombin generation. This led to the discovery that protein S acts as cofactor of tissue factor pathway inhibitor (TFPI) which stimulates the inhibition of factor Xa by TFPI ≈10-fold. The current review describes the background of the TFPI-cofactor activity of protein S as well as the rationale for the observation that the TFPI/protein S system particularly inhibits the TF pathway at low procoagulant stimuli.