Retinoic acid (RA) is a potent morphogen that has been shown to increase differentiation in some leukemic cell populations. RA has been used in treatment of some patients with acute myeloblastic leukemia (AML) and myelodysplastic syndromes. In previous experiments we had observed that RA may decrease the self-renewal of blast cells in established cell lines, and in our clinic RA has been tested as maintenance treatment in association with chemotherapeutic drugs. Accordingly, we asked if exposure of AML blast cells to RA affected their subsequent response to ara-C. We found that brief exposure to RA regularly increased the ara-C sensitivity of cells from two established AML cell lines. A similar, though less marked, effect was seen when the blast cells from one patient were tested directly; in a second instance, highly ara-C resistant blasts did not become sensitive when exposed to RA. Experiments using high specific activity tritiated thymidine did not disclose any changes in the proportion of AML cells in the DNA synthesis phase of the cycle at times when their responses to ara-C were changing. We interpret our findings as support for continuing efforts to integrate RA in the management of AML patients and suggest that the mechanism of ara-C sensitization may not depend on changes in the cell cycle.