Apoptosis is now recognized as a central process of development and disease, and it has been proposed as one of the mechanisms that may account for the lymphopenia seen in some diseases. In this study we measured spontaneous apoptosis and CD95 expression on different cell subpopulations from CVID patients, using flow cytometric techniques. We divided our patients into two groups according to their CD4+ and CD4+CD45RA+ cell counts. Our results clearly show increased spontaneous apoptosis and CD95 expression on the CD4+ and CD4+CD45RA+ subsets from lymphopenic CVID patients compared with normal subjects and disease controls. Interestingly, our lymphopenic CVID patients presented a profound reduction in absolute counts, mainly affecting the CD4+CD45RA+ subpopulation. We also found a statistically significant direct correlation between absolute numbers of CD4+CD45RA+ T cells and spontaneous apoptosis on the same subset in CVID patients, but attempts to induce CD95-mediated apoptosis were unsuccessful despite increased CD95 expression on CD4+ T cells. These findings suggest that apoptosis could be one of the mechanisms implicated in the significant lymphopenia present in these patients.