The differentiation-inducing effect of clinically applicable analogs of deoxyadenosine on myelomonocytic leukemia cells was examined. Monocytoid leukemia cells were more sensitive to the analogs than were erythroid or myeloid leukemia cells based on the inhibition of cell growth and induction of cell differentiation. Monocytoid leukemia cells were highly sensitive to combined treatment with 2'-deoxycoformycin (dCF) and 9-beta-D-arabinofuranosyladenine (Ara A) for inducing cell differentiation. Ara A induced the differentiation of monocytoid leukemia U937 and THP-1 cells at concentrations which were 1/1000-10000 of that at which it induced the differentiation of other cell lines in the presence of dCF. In combination with a low concentration of 1alpha,25-dihydroxyvitamin D3 (VD3), the induction of the monocytic differentiation was greater in monoblastic U937 cells. Adenosine deaminase-resistant analogs such as fludarabine (FLU) and cladribine (CdA) also induced the differentiation of human myelomonocytic leukemia cells, and these analogs synergistically enhanced the differentiation induced by all-trans retinoic acid (ATRA) or VD3. CdA was the most potent analog for inducing the differentiation of myeloid leukemia NB4 and HL-60 cells in the presence or absence of ATRA. These findings indicate that dCF + Ara A and CdA may be effective for the therapy of acute monocytoid and myeloid leukemia, respectively.