Canine histiocytic proliferative disorders include reactive diseases such as cutaneous and systemic histiocytosis and neoplastic diseases such as cutaneous histiocytoma and localized and disseminated histiocytic sarcoma (malignant histiocytosis). Their etiology and pathogenesis are unknown. Canine cutaneous and systemic histiocytosis target the skin and subcutis and have similar clinical behavior. Systemic histiocytosis also affects other organ systems. Clinicopathologic and phenotypic features of canine cutaneous and systemic histiocytosis were examined in this study. Canine cutaneous (18 cases) and systemic (26 cases) histiocytosis were characterized by angiocentric, pleocellular accumulations consisting of CD1+, CD11c+, MHC II+, CD4+, and Thy-1+(CD90) activated dermal dendritic antigen-presenting cells (APC) with admixed CD3+, CD8+, TCR&agr;&bgr;+T lymphocytes, and neutrophils. Hence, canine cutaneous and systemic histiocytosis represent two clinical manifestations of a reactive proliferation of dermal dendritic cells. Cultures and special stains failed to identify infectious agents. Canine reactive histiocytoses respond to immunosuppressive therapy (cyclosporine A or leflunomide). Therefore, immunedysregulatory mechanisms are likely to be involved. Spontaneous reactive histiocytoses are frequently seen in dogs, and they constitute an excellent model to study pathologic mechanisms involved in reactive proliferations of dermal dendritic APC.