A region of the N-terminal extracellular domain of the B-cell restricted cell differentiation antigen, CD19, has high amino acid sequence similarity to the receptor binding subunit B of verotoxin 1 (VT), an Escherichia coli elaborated cytotoxin, which specifically binds to the cell surface glycolipid, globotriaosylceramide, also known as the germinal center (GC) B-cell differentiation antigen, CD77. We have previously provided evidence of the association of CD19 and CD77 on the cell surface and in CD19-mediated homotypic adhesion of the Daudi Burkitt Lymphoma cell line, one normal counterpart of which is a subset of GC B cells. Evidence for the role of CD77 in CD19-induced apoptosis is now presented. Initial cell surface distribution, antibody-induced redistribution, internalization, and intracellular routing of CD19 were studied by confocal microscopy, IF, and postembedding IEM in CD77+ve and CD77-ve cells to investigate the possible role of CD77 in CD19 internalization and signaling. Daudi Burkitt's lymphoma cells were used as CD77+ve cells and as CD77-ve cells, Daudi mutant VT500 cells, and Daudi cells treated with PPMP, an inhibitor of CD77 synthesis, were used. Antibody ligated CD19 surface redistribution, internalization, and subcellular distribution of internalized CD19 was found to be different in CD77+ve and CD77-ve cells. A delay in internalization of antibody-CD19 complex was observed in CD77-ve cells. Internalized CD19 was targeted to the nuclear envelope in CD77+ve cells in a manner similar to that reported for VT, but not in CD77-ve cells. Internalization of CD77 by ligation with verotoxin prevented the internalization of ligated CD19. Induction of apoptosis following crosslinking of cell surface CD19 was greater in CD77+ve cells than in CD77-ve cells. The nuclear targeting of internalized CD19 and induction of apoptosis following CD19 crosslinking only in CD77+ve cells indicates a role for CD77-dependent CD19 retrograde transport from the B cell surface via the ER to the nuclear envelope in CD19-mediated signal transduction for apoptosis.