We have studied the effects of 2-chlorodeoxyadenosine (2-CdA) and melphalan on DNA synthesis and cell proliferation of five myeloma cell lines and one primary culture of highly purified myeloma cells. The DNA synthesis was estimated by thymidine incorporation and cell death was estimated by a coluorimetric assay sensitive to mitochondrial activity. The concentrations of 2-CdA giving 50% inhibition of DNA synthesis (ID50) in four cell lines were 8, 100, 500 and 2500 nM, whereas the corresponding concentrations of melphalan were 600, 600, 1000 and 7500 nM, respectively. In one cell line, the ID50 for melphalan was 400 nM, whereas 2-CdA apparently was without inhibitory effect and the ID50 was not reached. The ID50 for 2-CdA in the primary culture was 250 nM. When compared on a molar basis, 2-CdA had a more potent inhibitory effect than melphalan on four out of five myeloma cell lines. This is in contrast to clinical experiments which have shown lack of effect of 2-CdA in myeloma patients. Our study shows that 2-CdA has a marked heterogeneous effect on myeloma cell lines and opens up the possibility that a similar variation in sensitivity may also exist among myeloma cell clones in vivo.