We examined in vitro tritiated thymidine uptake by B cells from seven prolymphocytic leukemia (PLL), seven chronic lymphocytic leukemia (CLL), and four plasma cell leukemia (PCL) patients in response to culture with anti-human IgM antibody (anti-mu) and B-cell growth factor (BCGF). In contrast to the stimulatory effect observed in normal B-cell cultures, the divalent F(ab')2 anti-mu antibody uniquely inhibited the autonomous proliferation and induced marked cytotoxicity in six of seven PLL cell cultures independent of complement or Fc-receptor- mediated mechanisms. There was neither stimulation or inhibition of the slgM+ CLL or the slgM- PCL cells. The inhibitory effect on the PLL cells was observed at an anti-mu concentration below the stimulatory threshold for normal B cells. Significant impairment of trypan blue exclusion was delayed until 48 hours, with morphological cellular changes suggestive of a programmed cell death mechanism or apoptosis. The cytotoxicity was independent of the slgM-staining intensity or the autonomous and BCGF-augmented DNA synthetic activity of the PLL cells and was similar in patients with de novo PLL or with prolymphocytic transformation of CLL. Cells from a PLL patient were separated by elutriation into two fractions, a BCGF-unresponsive large “transformed” cell fraction with marked autonomous DNA synthesis and a smaller lymphoid cell subset with low 3H-thymidine uptake that could be augmented by BCGF. Both fractions were equally susceptible to the cytotoxic effect of anti-mu. These data suggest that certain slgM- bearing malignant B cells are susceptible to anti-mu-triggered cytotoxicity. They may represent the malignant counterpart of a “tolerogenic” normal B-cell subset, and the unique direct cytotoxicity of anti-mu may provide a therapeutic strategy specifically for PLL.