The effects of transforming growth factor-beta (TGF-beta) on the proliferative response of human B cells to the low molecular weight B cell growth factor (BCGF) have been investigated in this study. It was found that TGF-beta, at picomolar concentrations, strongly inhibited the BCGF-induced proliferation of anti-mu chain or Staphylococcus aureus Cowan I-activated human B cells and also of a BCGF-dependent cell line derived from a human lymphocytic nodular lymphoma. This inhibitory effect was detected in normal and serum-free culture conditions. The suppression was greatly reduced when TGF-beta was added to the culture one day after BCGF and could be reverted by removing TGF-beta from the culture medium. Since TGF-beta has been detected in supernatants from activated T cells, this factor may represent an important regulatory molecule in the feedback control of B cell activation.