Background: Heparin-induced thrombocytopenia (HIT) is a life-threatening thrombotic complication after heparin exposure. However, the role of ADAMTS-13 and von Willebrand factor (VWF) in the disease process and outcomes of HIT is not known. Objective: To determine the potential role of ADAMTS-13 and VWF in hospitalized patients suspected with HIT. Methods: Associations of the HIT tests, ADAMTS-13 activity, and VWF antigen or activity with other clinical parameters and outcomes in the patients suspected with HIT were determined. Results: Of 261 patients, 87 (33.3%) were positive and 174 (66.7%) were negative for a HIT antibody determined by an enzyme immunoassay (EIA). Of these 87 EIA+ patients, 31 (35.6%) were also positive but 56 (64.4%) were negative for serotonin-releasing assay (SRA). There was no statistically significant difference among all three groups (i.e., EIA–, EIA+/SRA+, and EIA+/SRA–) as to their demographic features, reasons for admission to the hospital, type of procedures performed, and in-hospital mortality. Compared to those in the healthy controls, plasma ADAMTS-13 activity in patients suspected with HIT was significantly lower but plasma VWF antigen (VWFAg) and activity (VWFAc) in these patients were significantly higher. While there was no statistically significant difference among all three groups regarding plasma levels of ADAMTS-13 activity, VWFAg, and VWFAc, plasma levels of ADAMTS-13 activity <50% or the low ratios of ADAMTS-13 activity to VWFAg (or VWFAc) are highly predictive for a 90-day mortality rate, particularly in the EIA+SRA+ group. Conclusions: These results demonstrate that relative deficiency of plasma ADAMTS-13 activity in hospitalized patients suspected with HIT is common, which may contribute at least in part to the adverse outcomes in this patient population, particularly in those with true HIT.