The biological role in vivo of the homologous CD3 gamma and delta invariant chains within the human TCR/CD3 complex is a matter of debate, as murine models do not recapitulate human immunodeficiencies. We have characterized, in a Turkish family, two new patients with complete CD3 gamma deficiency and SCID symptoms and compared them with three CD3 gamma-deficient individuals belonging to two families from Turkey and Spain. All tested patients shared similar immunological features such as a partial TCR/CD3 expression defect, mild alpha beta and gamma delta T lymphocytopenia, poor in vitro proliferative responses to Ags and mitogens at diagnosis, and very low TCR rearrangement excision circles and CD45RA(+) alpha beta T cells. However, intrafamilial and interfamilial clinical variability was observed in patients carrying the same CD3G mutations. Two reached the second or third decade in healthy conditions, whereas the other three showed lethal SCID features with enteropathy early in life. In contrast, all reported human complete CD3 delta (or CD3 epsilon) deficiencies are in infants with life-threatening SCID and very severe alpha beta and gamma delta T lymphocytopenia. Thus, the peripheral T lymphocyte pool was comparatively well preserved in human CD3 gamma deficiencies despite poor thymus output or clinical outcome. We propose. a CD3 gamma >> CD3 gamma hierarchy for the relative impact of their absence on the signaling for T cell production in humans.