Butyrate, at concentrations greater than 0.75 mM, induces hemoglobin accumulation in murine erythroleukemia cells (MELC). At concentrations below 0.75 mM, butyrate inhibits hemoglobin accumulation induced by hexamethylene bisacetamide (HMBA) as well as HMBA induced commitment to terminal cell division. The blocking of HMBA induced differentiation does not result from growth inhibition. When cells were exposed to HMBA and butyrate for 4 days and then both inducers were removed, the cells did not terminally divide. On the other hand, cells exposed to HMBA for 4 days, with subsequent removal of HMBA, did go on to terminally divide. Thus, butyrate blocks the ability of HMBA to accumulate the intracellular signals for terminal cell division. A 48-h pretreatment of cells with butyrate did not inhibit the ability of subsequent HMBA treatment, after butyrate removal, to induce terminal cell division. These results might suggest that cells do not generate a memory of exposure to HMBA in the presence of butyrate or a memory of exposure to butyrate when used as a pretreatment under these conditions. HMBA, at concentrations below 1.0 mM, does not induce MELC differentiation, but such concentrations actually enhance dimethyl sulfoxide induced differentiation of MELC. Equimolar concentrations of short chain fatty acids (1 to 7 carbons) were tested for their ability to block HMBA induced differentiation of MELC. Butyrate and valerate (4 and 5 carbons, respectively) had blocking activities similar to each other, whereas the other fatty acids exhibited little or no blocking of HMBA induced differentiation.