Due to its recognized, though insufficiently defined, graft-versus-tumor (GVT) activity, allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only curative treatment available for patients with hematologic malignancies including B-cell chronic lymphocytic leukemia (CLL). GVT activity, as well as its counterpart graft-versus-host-disease (GVHD), is believed to be mediated primarily by alloreactive donor T-cells. Shifting the focus to another component of the adaptive immune system, we are investigating whether alloreactive antibodies derived from donor B-cells may also have a role in GVT activity. We developed a sensitive flow cytometry assay for detection of post-transplant serum antibodies against cell surface antigens expressed on CLL tumor cells. Post-transplant sera collected from CLL patients at defined time points after allogeneic HSCT showed significant binding to CLL tumor cells but not normal B-cells. Pre-transplant sera, donor sera, and control sera were negative. The alloreactive antibody response correlated with the disappearance of circulating CLL tumor cells, suggesting an antigen-driven immune response. In order to identify the alloreactive antibodies and subsequently the cell surface antigens they recognize, we are currently generating human antibody libraries from post-transplant PBMCs for selection on primary CLL tumor cells as well as CLL tumor cell lines by phage display.