It has been suggested that MHC class II molecules can transduce signals required for B-cell activation. Enhancement or inhibition of B-cell stimulation by anti-MHC class II molecule antibodies has likewise been reported. The study of B cells from patients with a combined immune deficiency due to a defective expression of MHC class II genes provides a useful tool for approaching the functional role of B-cell HLA class II molecules. We have thus analyzed the specific and nonspecific, cognate and noncognate B-cell activation of genetically HLA class II-deficient lymphocytes. B lymphocytes from 14 tested patients were able to synthesize RNA following stimulation with ionomycin and phorbol myristate acetate or anti-mu antibodies and with mannan, a T cell-independent polysaccharidic antigen. They were also able to synthetize DNA following the addition of ionomycin and PMA or of anti-mu antibodies in the presence of recombinant interleukin 2. Pokeweed mitogen failed to induce B-lymphocyte terminal differentiation into immunoglobulin-producing cells in the presence of normal T lymphocytes, while a combination of anti-CD2 antibodies were capable of triggering IgG synthesis. B-cell activation, whatever the condition used, did not induce HLA class II expression. Mannan-specific T cell-dependent antibody production (IgM) was detected in 6 of 14 patients. Anti-influenza virus antibody production was always found absent. These results are compatible with the hypothesis that B-cell activation events that do not require a cognate interaction with T cells can occur in the absence of HLA class II molecule expression, while the absence of HLA class II molecule expression prevents T-B cognate interaction.