Castleman's disease is an atypical lymphoproliferative disorder characterized by the prevalence of B CD5-positive cells in the marginal zone. Autoimmune manifestations have often been reported, but the association of Castleman's disease with systemic autoimmune syndromes has been rarely described. However, many authors stress the difficulties in distinguishing between connective tissue disease and Castleman's disease in most cases. To clarify this issue, we describe a patient and review the literature reports of all cases of Castleman's disease associated with a connective tissue disease. A 19-year old woman presented with autoimmune thyroiditis and polymyositis. Seven years after the onset she developed a systemic inflammatory flare and a burst of autoimmunity, followed by generalized lymphoadenopathy. A mediastinal lymph node biopsy led to the diagnosis of Castleman disease of mixed type. Chemotherapy was given, with rapid response of the lymphoproliferative disorder but persistence of the underlying autoimmune disorder. The plasma concentration of B-lymphocyte stimulator (BLyS) was high (13.3 ng/mL) at the diagnosis of Castleman's disease. It fell dramatically after chemotherapy (4.97 ng/mL), even though it remained just above the mean BLyS value found in healthy blood donors (3.37+/-0.78 ng/mL).Castleman's disease can present autoimmune traits. In our patient, Castleman's disease complicated the course of a connective tissue disorder several years after the onset. We hypothesize that chronic stimulation of B-cell clones, particularly CD5+, by BLyS could favor the development of both autoimmune diseases and a broad range of lymphoproliferative disorders (such as Castleman's disease). This is the first report of increased BLyS levels in a patient with Castleman's disease, supporting a possible pathogenetic role of BLyS in the development of an autoimmune disorder and of a B lymphoproliferative disorder years later.