Recent data have shown a definite relationship between complement and lymphocytes. Genetic studies have demonstrated close linkage between the genes controlling synthesis of complement components C4 and C2 and the major histocompatibility complex. Working in a complement-free environment, we studied the effect of purified human complement components, individually and in various combinations, upon in vitro proliferative responses of human lymphocytes to mitogens and antigens. It was found that the early complement components C1, C4 and C2, together, modulate lymphocyte responses to these various stimuli. In general, doses up to 1,000 effective molecules of each component per lymphocyte enhanced the cells' responses to both mitogens and antigens. Higher doses, up to 3,000 effective molecules of each per lymphocyte, progressively inhibited the cells' responses to the mitogens whereas responses to the antigens showed continued enhancement. This effect was removed by prior heat-inactivation of the complement. It persisted when the cells were exposed to C1, C4 and C2 for 1 hr, then washed and cultured with mitogen. It required active C1 in the fluid-phase prior to addition of C4 and C2. It correlated with the amount of activated C2 to which the cells were exposed. Enriched populations of T and B cells were affected equally.