In an attempt to develop a suitable model for increasing the yield of human anti-HLA mAbs, we have used mice with SCID for i.p. injection of two human-mouse heterohybridomas. HMP1 hybridoma secretes a DQB1*0201 allele-specific human mAb whereas HMP12 secretes a human mAb recognizing the DRB1*1101, 1102, 1103, and 1104 alleles. Both hybridomas could be grown in SCID mice as localized tumors with no apparent alteration in the morphology of the cells or in the immunoglobulin secretion. Ascitic fluid was produced that showed a 600- to 1000-fold increase in monoclonal antibody cytotoxic titer as compared with that obtained in tissue culture. HLA-DQB1* and DRB1* alleles recognized by ascites and supernatants from SCID-derived cultures were analyzed by microlymphocytotoxicity assay on a small panel of B-lymphoblastoid cell lines. The results show that HLA specificity was retained after in vivo passage.