Iron and zinc are known to have immunomodulatory functions. In the present work, iron (FeC6H5O7) and zinc (ZnCl2) were tested in comparison to nickel (NiCl2) and cobalt (CoCl2) for their effect on six different surface molecules known to be involved in recognition and activation processes, namely CD4, CD2, CD3, CD8, HLA-ABC, and HLA-DR. Iron was seen to down-modulate expression of the CD4 and the CD2 molecules on the surface of T-lymphocytes, as indicated by a decrease in the mean fluorescence intensity measured by FACS analysis. None of the other T-cell molecules tested were significantly affected. In addition, the iron-mediated CD4 down-modulation reached its lowest level by 12 hr, at which time a striking decrease in the percentage of CD4+, but not CD8+, cells was observed. This decrease was followed by a gradual recovery starting at 18 hr and reaching its highest level at 48 hr. When cells were treated with other metal salts, none of those effects were observed. The present results suggest that iron may play a regulatory role in processes of T-cell recognition and T-cell activation by selectively down-modulating T-cell molecules known to be involved in these processes.