The clinical spectrum of leprosy is related to patients' immune responses. Non-responsiveness towards Mycobacterium leprae (ML) seems to correlate with a Th2 cytokine profile. The reason for such a polarized immune response remains unclear. The C-type lectin, DC-SIGN, expressed by subsets of dendritic cells (DCs) and macrophages, has previously been associated with Th2 responses. Here we show abundant DC-SIGN expression in lepromatous but not borderline tuberculoid leprosy, in both HIV-positive and HIV-negative patients. Moreover, we demonstrate that DC-SIGN can act as an entry receptor for ML, as it does for M. tuberculosis, through the cell wall component lipoarabinomannan. DC-SIGN is expressed on virtually all ML-containing cells, providing further evidence for its role as a receptor. DC-SIGN may therefore be induced on macrophages in lepromatous leprosy and may then contribute to mycobacterial entry into these cells.