A recent report that activated protein C (APC) resistance interferes with functional protein S (PS) assays prompted us to re-investigate two pedigrees previously diagnosed as having functional PS deficiency. APC resistance was demonstrated in all individuals with apparent functional PS deficiency. The latter diagnosis was shown to be due to the assay being non-linear, functional protein S becoming normal at higher dilutions. This observation, taken in conjunction with results of in vitro recovery studies with purified PS, leads us to conclude that APC resistance was the primary disorder in both pedigrees. The misdiagnosis of APC resistance as functional PS deficiency can be prevented by performing the PS assay at several dilutions, including concentrations lower than those recommended by PS assay manufacturers. Subjects previously diagnosed as having functional PS deficiency should be re-investigated for APC resistance.