In normal T cells, an anti-CD28 MoAb (Kolt-2) will synergize with the mitogenic stimuli phytohaemagglutinin (PHA), anti-CD3 (OKT3) or a combination of anti-CD2 antibodies (OKT11 and GT2) in the induction of DNA synthesis. A subgroup of patients with common variable immunodeficiency (CVID) show a defect in DNA synthesis by T cells stimulated in vitro with the above mitogens. We have now investigated whether anti-CD28 will correct the defect. This strategy partially restored DNA synthesis, providing evidence that the CD28 co-stimulatory pathway in CVID T cells is normal. Ligation of CD28 acts through co-stimulating IL-2 secretion. The natural ligand (B7) for CD28 on antigen-presenting cells from CVID patients is expressed normally. We conclude that the defect in CVID T cells lies in pathways that lead to transcription of the IL-2 gene other than that induced by ligation of CD28 with Kolt-2.