In this study we investigated the distribution of IgG4+ plasma cells and regulatory T (T(REG)) cells, a major regulator of IgG4 production, in nodal and extranodal Rosai-Dorfman disease (RDD). Twenty-six specimens (15 nodal, 11 extranodal) were examined, with reactive lymph nodes and site-matched extranodal specimens as controls. Overall, 84.6% (22/26) of the specimens showed various degrees of sclerosis (7 mild, 8 moderate, and 7 severe). Nineteen cases (73.1%) exhibited more than 10 IgG4+ cells/0.060 mm(2) (photographed area at ×40), and 8 cases (30.8%) showed more than 40% of IgG+ cells being IgG4+. Only 1 control case exhibited more than 10 IgG4+ cells/0.060 mm(2) (P < .05). The number of T(REG) cells was comparable between nodal RDD and controls, whereas extranodal RDD exhibited significantly higher numbers of T(REG) cells than controls. These findings demonstrate that a subset of RDD shows features of IgG4-related disease and indicate an overlap between certain aspects of the 2 diseases.