Human monoclonal antibodies (hu-mAbs) of predetermined specificity and isotype are potentially important for a variety of applications, including therapy and diagnosis. Their efficient generation, however, is still hampered by technical difficulties. Even the most established approaches to the generation of hu-mAbs, i.e., B cell immortalization by Epstein-Barr virus (EBV) and/or fusion with appropriate myeloma cell lines, are characterized by a relatively low efficiency. It has been shown that expression of activated Ha- or N-ras oncogenes causes the malignant transformation and plasmacytoid differentiation of EBV-immortalized lymphoblastoid cell (LC) lines, suggesting that activated ras oncogenes can convert LC lines into effective hu-mAb producers. We have used retroviral vector-mediated gene transfer to introduce an activated Ha-ras (v-ras) oncogene into four distinct LC lines producing hu-mAbs of different classes (IgM and IgG) and specificities (to human insulin, human thyroglobulin and rabies virus glycoprotein). The cloning efficiency and antibody secretion of these ras-transformed LC (ras-LC) lines were compared with those of the hybrid LC (hyb-LC) lines generated by fusing the same parental LC lines with the Ig non-secretor F3B6 human-mouse hybrid cells. ras-LC lines were comparable to their hybrid counterparts in either parameter tested. This, together with the relatively higher efficiency of the method, suggests that ras transformation may constitute a valid alternative to the currently available technologies for hu-mAbs production from LC lines.