The occurrence and distribution of distinct receptors for three C3 fragments on purified human blood lymphocytes were studied by rosette formation. Indicator cells were bovine, chicken, or sheep erythrocytes (E) bearing up to 100,000 molecules of human C3b (EC3b) without antibody. EC3b was converted to C3bi-bearing-E (EC3bi) with purified C3b inactivator (factor I) and β1H (factor H), and to C3d-bearing E (EC3d) by treatment of EC3bi with trypsin. Using bovine E (E(b)) as indicators, ~11% of the lymphocytes bound E(b)C3b, 6% E(b)C3bi and 2% bound E(b)C3d. Fractionation of the lymphocytes by adsorption to monolayers of C3-fragment-bearing E(b) or by rosetting indicated that most of the cells with receptors for C3b were distinct from those having receptors for C3bi and/or C3d. Cells from two lymphoblastoid cell lines (Raji and Daudi) formed strong rosettes with either EC3bi or EC3d. A fraction of the Raji cells, but not of Daudi cells formed rosettes with EC3b, which were weak. 51Cr-labeled E was used as a target in antibody-dependent, lymphocyte-mediated cytotoxicity (ADCC). In the absence of antibody, C3-fragment-bearing E was not lysed by the lymphocytes. However, at suboptimal concentrations of IgG anti-E antibody, ADCC of C3-fragment-bearing E was strongly enhanced. The enhancing capacity of the fragments occurred in the order of C3bi > C3d ≥ C3b. In addition, C3-fragment-bearing cells inhibited the lysis of antibody-coated cells not bearing C3 fragments. Inhibition ranked in the same order as enhancement. It is concluded that target cell bound C3 fragments enhance ADCC by improving contact between target cells and those effector cells which have C3 receptors. Cell-bound C3 fragments inhibit ADCC of C3-free targets by impeding their contact with such effector cells. It is proposed that certain lymphocytes are capable of interacting with C3bi in addition to C3b and C3d and that C3bi and C3d have a greater regulatory effect on their cytolytic function than C3b.