Much remains to be clarified regarding the functional capacities of the two major reciprocal subsets of human CD4+ cells which we interpret to be naive and memory cells. CD4+ naive (CD45RA+, LFA‐3−) and memory (CD45R0+, LFA‐3+) cells were rigorously purified by immunomagnetic negative selection. Their proliferation was measured in response to four protocols of receptor‐mediated activation: soluble anti‐CD3 mAb, plastic‐immobilized anti‐CD3 mAb, activating pairs of anti‐CD2 mAb, and “superantigens” staphyloccocal entero‐toxins A and B (SEA and SEB). Naive cells proliferated much less than memory cells to each of these four regimens although their capacity to respond was demonstrated by strong PHA‐induced proliferation. Although three of the regimens depend on autologous monocytes, poorer naive cell responses are also observed to anti‐CD3 mAb immobilized on plastic in the absence of monocytes; this implies an intrinsic hyporesponsiveness of naive cells, independent of theirpotentially weaker interaction with monocytes. Naive cells proliferated less than memory cells to superantigens SEA and SEB over a wide dose range; this assumes particular importance because such superantigens are believed to more closely mimic antigen‐specific stimulation than anti‐CD3 mAb. The possibility was explored that hyporesponsiveness of naive cells reflects the fact that naive cells require additional co‐stimuli to facilitate their activation. In support of this concept, we observed that proliferation of naive cells to anti‐CD3 mAb and SEA or SEB (but not to anti‐CD2 mAb pairs) was consistently enhanced by pre‐activation of monocytes present in the culture. Naive cell proliferative responses were augmented further in cultures supplemented with interleukin (IL) 1β and IL 6 or exposed to the co‐stimulating mAb anti‐CD28 and anti‐CD44. The pattern of augmentation was dependent on the specific triggering regimen: anti‐CD44 mAb was particularly effective in augmenting the response to superantigens, anti‐CD28 mAb for the anti‐CD3 response and IL 1β/IL 6 for that induced by anti‐CD2 mAb pairs. With particular combinations of stimulus/co‐stimuli naive cell proliferation was as strong as that of memory cells. We interpret these findings to indicate that naive cells are capable of responding to antigen, but that such responses are critically dependent on the available co‐stimuli in vivo.