In some infants with Down's syndrome, the circulating mononuclear population, when viewed with conventional and electron microscopy, contains many cells that closely resemble leukemic blast cells. In contrast with true leukemia, however, most of these infants with the “leukemia like reaction in Down's syndrome” (LLR-DS) enter spontaneous remissions. We therefore investigated the natural resistance of such infants to hematological malignancy in vitro by means of natural killer cell assays. Mean natural killer cell determinations in four infants with LLR-DS were 17.5 ± 9.2% and 37.6 ± 18.5% against K-562 and Molt-4 target cells, respectively, at diagnosis. Later, during remission, these values were 34.3 ± 14.3% against K-562 and 32.2 ± 15.6% against Molt-4. The mean percentage lysis of Molt-4 both at diagnosis and during remission was greater (p < 0.05) in LLR-DS than in children with acute lymphocytic leukemia and acute myelogenous leukemia at diagnosis. Natural killer cell activity levels in these LLR-DS patients were similar to levels obtained in other infants with Down's syndrome who were hematologically normal, as well as levels obtained in normal control specimens. Two of these LLR-DS patients progressively developed acute myelogenous leukemia with ultrastructural abnormalities several months later; one of these also developed another karyotype abnormality. Both remain in long-term remission exceeding 48 months.