In suspected cases of disseminated intravascular coagulation, concurrent elevation of both fibrin(ogen) degradation products (FDPs) and D-dimer levels aids in confirming the diagnosis. This pattern of results reflects the action of plasmin proteolysis of cross-linked fibrin polymers as well as fibrinogen. We report the case of a patient with human immunodeficiency virus (HIV) and Castleman disease who presented with a high-positive D-dimer level and a negative FDP level in the course of a workup for disseminated intravascular coagulation. This finding suggested the possibility of either a false-positive D-dimer or a false-negative FDP level. To investigate the former, a Western blot was performed on the patient's serum to determine the presence of the D-dimer. No D-dimer band was visualized on the Western blot, confirming the false-positive nature of the D-dimer result. Insufficient quantity of patient serum, however, prevented further investigation into the etiology of this result. The false-positive D-dimer result is likely attributable to interference caused by the patient's Castleman disease-associated monoclonal gammopathy, a phenomenon that has been reported in other immunoassays. As the development of lymphoproliferative disorders is especially common within the HIV population, and hypergammaglobulinemia in Castleman disease is particularly common, clinicians should be aware of this phenomenon when the laboratory findings do not fit the clinical picture. Although it is rare, recognition of potential paraprotein interference in immunoassays will help avoid undertreatment or overtreatment of patients based on erroneous laboratory results.