Previous studies on peritoneal plasmacytomas (PCTs) in BALB/c (C) mice suggested that the enforced expression of the death repressor BCL2 in B cells might facilitate the malignant transformation of aberrant B cells containing Myc-activating T(12;15) translocations, generating an improved model of plasmacytomagenesis. To investigate this hypothesis, we backcrossed a human BCL2 transgene onto strain C and performed a PCT induction study with pristane in the newly generated C.BCL2 congenics. In specific pathogen-free-maintained C.BCL2 mice, PCT incidence (19 of 34, 56%) was 24 times higher than in specific pathogen-free-maintained C mice (1 of 44, 2.3%), and tumor onset (113 days) was half that of conventionally maintained C mice (220 days). BCL2 transgenic PCT harbored T(12;15) translocations (12 of 12 tumors) with an unusual clustering of translocation breakpoints in the near 5' flank of Myc (4 of 5 tumors, 80%). Five tumors contained coexisting T(12;15) and T(6;15) translocations (not observed in >300 karyotyped PCTs from conventionally maintained C mice). BCL2 transgenic C57BL/6 mice exclusively developed B lymphomas (11 of 20, 55%) that also contained T(12;15) translocations (11 of 11 cases) with breakpoints in the near 5' flank of Myc (five of five tumors). We conclude that BCL2 accelerates PCT with novel Myc-activating translocations independently of environmental antigen stimulation. Accelerated plasmacytomagenesis in strain C.BCL2 may be useful for designing and testing BCL2 inhibition strategies in human plasma cell tumors overexpressing BCL2, such as Waldenström's macroglobulinemia and multiple myeloma.