Signal transduction via HLA class-II antigens has been studied using human resting B lymphocytes and monoclonal anti-HLA class-II antibodies. An increased intracellular calcium flux, phosphatidylinositol biphosphate hydrolysis and activation of protein kinase C have all been observed following signal transduction via HLA-class-II molecules. The interaction of HLA-class-II-mediated signalling with sIg-mediated signalling has been studied using a non-mitogenic anti-sIg. This combination provides a model for T-cell-dependent antigenic stimulation. The results demonstrate that stimulation via HLA class-II antigens permits a proliferative response to an otherwise non-mitogenic anti-sIg and that this effect is not restricted to one HLA class-II isotype. These data suggest that HLA-class-II-mediated signalling is important in responses to T-cell-dependent antigens.