Natural killer cell activity and alterations in cytotoxicity after culture with streptococcal blastogen A and phytohemagglutinin (PHA) were examined in patients with inactive rheumatic heart disease (RHD) and control patients. Natural cytotoxic activity of mononuclear cells (MNC) did not differ between RHD and control patients with either peripheral blood or tonsils. In cultured blood MNC the level of cytotoxic activity stimulated by blastogen A was significantly greater in patients with RHD at all effector:target cell ratios. These differences in cytotoxic activity were not observed with cultured tonsillar MNC. In similar experiments with a different group of patients, culture with PHA or blastogen A both produced a significantly greater increase in cytotoxic activity in blood MNC from patients with RHD. The increase was significantly lower with PHA than with blastogen A. The ability of mitogens to differentially augment cytotoxic activity in cells from the blood of patients with RHD implies that a population of cells exists in these patients that could be activated during acute rheumatic fever to play a role in pathogenesis.