In factor V (FV) Cambridge (Arg306Thr) and Hong Kong (Arg306Gly), a cleavage site for anticoagulant activated protein C (APC), which is crucial for the inactivation of FVa, is lost. Although patients carrying FV Hong Kong have a normal APC response, those with FV Cambridge were reported to be APC resistant. To elucidate the molecular characteristics of the 2 FV mutants, we recreated them in a recombinant system and evaluated their functional properties. The 2 FV variants yielded identical APC resistance patterns, with APC responses being intermediate to those of wild-type FV and FV Leiden (Arg506Gln), which is known to be associated with the APC resistance phenotype. In the absence of protein S, APC mediated FVa inactivation curves obtained with the 2 variants were identical, resulting in partial FVa inactivation. In the presence of protein S, both FVa variants were almost completely inactivated because of protein S stimulation of the cleavage at Arg679. In a FVIIIa degradation system, both FV variants demonstrated slightly impaired APC cofactor activity. The ability of APC to cleave at Arg506 and at Arg679 in FVa Cambridge and Hong Kong and the slight decrease in APC cofactor activity of the 2 FV variants may explain the low thrombotic risk associated with these Arg306 mutations. In conclusion, we demonstrate that recombinant FV Cambridge and Hong Kong behave identically in in vitro assays and provide a mechanism for the low thrombotic risk associated with these FV mutations.