Cultured human lymphoid cells sensitized with human histocompatibility (HL-A) antibodies were able to activate the human complement system in vitro. Some HL-A alloantisera selectively activated the alternate complement pathway while other antisera activated only the classical pathway. A third group of alloantisera was equally able to initiate complement action by way of either pathway. The mechanism of complement activation did not correlate with the HL-A antigen present on the cells or the HL-A specificity of the alloantisera, indicating that the antigenic determinants or distribution on the cell surface play on direct role in selecting the pathway of activation. In this completely homologous system the alternate pathway was found to have the same cytolytic potential as the classical pathway. Thus, an altered or damaged membrane is not a prerequisite for the production of cytolytic damage by the alternate pathway. A complete understanding of the mechanism of interaction of membrane bound antigens and antibodies with the complement system may provide a versatile tool for the investigation of membrane antigen expression.