CD47 is highly expressed on various hematopoietic malignancies, and enables cancer cells to avoid immunosurveillance. Its ligand, thromobospondin-1 (TSP-1) is a multifunctional protein, and CD47/TSP-1 interactions promote tumor progression in various malignancies. In this study, we investigated roles of TSP-1 and CD47 in cutaneous T-cell lymphoma (CTCL). Flow cytometric analysis and immunohistochemistry showed that CTCL tumor cells and CTCL cell lines (Hut78, HH, and MyLa cells) overexpressed CD47 compared with normal CD4+ T cells. Overexpression of CD47 was partially induced by high c-Myc expression in CTCL tumor cells. TSP-1 mRNA expression levels in CTCL lesional skin were higher than those in normal skin and correlated with increased risk of disease-related death. Moreover, TSP-1 was expressed on CTCL tumor cells by immunohistochemistry. Serum soluble TSP-1 levels in patients with Sézary syndrome were significantly elevated. TSP-1 promotes proliferation and survival of CTCL tumor cells, which is inhibited by anti-CD47 neutralizing antibody or CD47 knockdown. Stimulation with TSP-1 also induces cell migration and in vivo growth. These effects were mediated by phosphorylation of ERK1/2 and AKT and expression of survivin. Collectively, our findings prompt a novel therapeutic approach to CTCL based on discovery that CD47/TSP-1 interactions play important roles in progression of CTCL.