Investigation of recurrent venous thromboembollc events In a 46-year-old man with progressive IgG kappa (total serum IgG, 74.3 mglml) multiple myeloma revealed profound reductions In free protein S (PS) antigen (<0.1 U h l ) and PS activity (0.33 Ulml). Total PS antigen, protein C, antlthrombln 111, and C4b-binding protein levels were within normal ilmlts. The patient had no family history suggestive of a congenital PS deficiency and no history of thrombosis predating the diagnosis of his plasma cell dyscrasla. Patient IgG was Isolated from serum using a protein A-sepharose affinity column and characterized. PSdependent clotting assays (Staclot Protein s, Diagnostica Stago, Asnleres sur-Seine, France) performed on normal pooled plasma mixed with dilutions of patient lgG (0.0-33.0 mgml) revealed a dosedependent neutralization of PS activity by 43%. Total and free PS antigen levels were measured using Laurel1 rocket electrolmmunodlffuslon (Assera-Plate Protein S, Diagnostlca Stago), which revealed a similar dosedependent reduction In free PS antigen but preserved normal total PS antigen. Free PS antigen was reduced by 77% to 0.23 Ulml using an IgG concentration (16.5 mglml) less than onefourth of that of the patient at time of serum collection. Specific binding of the patient IgG to commercially available purified human PS was demonstrated by Western lmmunoblot analysis. Whereas acquired free PS deficiency has been prevlously reported in association with nephrotlc syndrome, Inflammatory bowel disease, HIV infection, and varicella infee tlon, this Is the first reported case of a hypercoagulable syndrome associated with acquired free PS deficiency and multiple myeloma.