Bacillus Calmette-Gue ´rin (BCG) mycobacteria have been used as adjuvant in the active immunotherapy of various human cancers. In addition, dendritic cells, which are the most potent antigen-presenting cells, have been shown to be capable of initiating anti-tumor immune responses. Here we investigated the effects of BCG on dendritic cells cultured from human blood. Addition of BCG resulted in rapid homotypic adhesion of dendritic cells. Moreover, BCG concentrations ranging from 10 4 to 10 6 bacteria/ml enhanced expression of the dendritic-cell-maturation antigen CD83 and of the T-cell co-stimulator CD86 (B7-2) in a dose-dependent manner. Concomitant with the increase of CD83 and CD86 expression, the cells lost the ability to capture soluble antigens, as determined by the exclusion of fluoresceinated Dextran molecules. Strikingly, the same dosages of BCGbacteria stimulated TNF-a-gene transcription and TNF-aprotein release from dendritic cells in a dose-dependent fashion. BCG infection of dendritic cells in the presence of a neutralizing antibody directed against TNF-a inhibited CD83 expression by more than 50% indicating that the BCGinduced maturation of dendritic cells was at least partially mediated by dendritic-cell-derived TNF-a. The finding that BCG activates the most potent antigen-presenting cells reveals a plausible immunological mechanism of the occasionally observed anti-tumor activity of BCG.