Rosai-Dorfman disease (RDD) is a rare histiocytosis with heterogenous clinical features. In this study, we characterized the histologic and phenotypic features in 33 RDD patients to better define the pathologic diagnosis. Cases included 24 patients with extracutaneous disease ("R"group), and 9 patients with lesions limited to the skin or subcutaneous tissue ("C"group). We identified OCT2 as a novel marker for the monocyte-macrophage phenotype of RDD, expressed in 97% of RDD cases. In contrast, OCT2 expression was seen in 0% of Erdheim-Chester disease cases and 6.7% of Langerhans cell histiocytosis cases. Other markers useful in the diagnosis of RDD included S100 (100%), CD163 (88%), and cyclin D1 (97%). In a subset of cases, RDD showed moderate to strong expression of factor 13a (30%), p16 (64%), and phosphorylated extracellular signal-regulated kinase (45%); RDD was uniformly negative for ZBTB46, CD1a, and langerin. Within the "R group"of RDD, increased expression of factor 13a or phosphorylated extracellular signal-regulated kinase showed a statistically significant association with multifocal disease (P<0.05). Identification of the unique monocyte-macrophage phenotype of RDD with OCT2 expression furthers our understanding of this complex disease and allows for more uniform classification.