CD4 cell subsets, CD4+CD45R+ (CDw29-) cells and CD4+CD45R- (CDw29+) cells, can be differently triggered by various stimuli and possess distinct functions. In the present study, cell activation in CD4+CD45R+ and CD4+CD45R- subsets mediated by CD3-Ti antigen-receptor complex or CD2 molecule were examined by using anti-CD3 antibody or pairs of anti-CD2 antibodies (anti-T11(2) and anti-T11(3) antibodies). The results showed that CD4+CD45R+ cells were preferentially activated through the CD2 pathway, whereas both subsets were equally activated through the CD3-Ti antigen-receptor pathway when a second signal such as monocytes or interleukin 2 was present. The different responsiveness of CD4+CD45R+ and CD4+CD45R- subsets through the CD2 molecule did not appear to be due to differences in the distribution or number of T11(2) and T11(3) determinants. These data suggest that some part of the functional diversity of CD4 cell subsets might be explained by the differences in cell activation through the CD2 molecule.