The lipid metabolism is important in the regulation of cell proliferation. We have examined effects of a fatty acid analogue, tetradecylthioacetic acid (TTA), on the functional phenotype of native, human AML cells. TTA inhibited AML blast proliferation in the presence of single cytokines (GM-CSF and SCF: P > 0.05, 35 patients with detectable proliferation) and a combination of cytokines (P < 0.005, n = 21). This antiproliferative effect was generally stronger than for the normal fatty acid palmitic acid (PA). Both TTA and PA increased the secretion of tumor necrosis factor alpha (TNFalpha) (P < 0.05, 27 patients with detectable cytokine release), but only PA increased interleukein 1beta (IL-1beta) release (P < 0.005, n = 34). AML blast populations varied significantly in their levels and activities of metabolites and enzymes characterizing oxidative status and fatty acid metabolism, and there was no significant correlation between the intrinsic oxidative status and the effects of PA and TTA on blast proliferation. Although TTA reduced the proliferation of mitogen-stimulated normal T cells derived from healthy individuals (P < 0.05, n = 8), no adverse effects were seen on peripheral blood cell counts (reticulocytes, platelets, total white blood cells, differential leukocyte counts) for healthy volunteers receiving TTA (oral administration of 1000 mg/day for 7 consecutive days). Our results suggest that TTA can inhibit AML blast proliferation through pathways that are unrelated to autocrine cytokine secretion and intrinsic oxidative status.