Scedosporium prolificans (SP) is an emerging opportunistic dematiaceous mould that causes serious infections in immunocompromised patients. Antifungal activities of human polymorphonuclear (PMN) and mononuclear (MNC) leukocytes against five SP isolates and Aspergillus fumigatus (AF) were evaluated. While monocyte-derived macrophages (MDM) phagocytosed conidia of both organisms comparably, they inhibited the germination of S. prolificans conidia less efficiently than those of A. fumigatus. Unopsonized hyphae of SP strains decreased the superoxide anion (O2-) produced by both PMN and MNC, whereas opsonized hyphae significantly stimulated it. In comparison to AF, phagocytes generally exhibited equal oxidative burst in response to SP. While PMN- and MNC-induced hyphal damage was similar among SP strains, phagocytes tended to damage SP hyphae to an equal or higher degree than AF hyphae. The susceptibility of SP to phagocytes contrasts with its high resistance to antifungal agents and may be related with the very low pathogenicity of the mould.