By selective breeding we have recently obtained two discrete sublines of rats that differ in serotonin content in their platelets. As both serotonin and platelets may influence, or even take part, in immune reactions, we tested in this work the natural cytotoxicity in rats with constitutionally different platelet serotonin levels (PSL). Rats with low platelet serotonin level (mean +/- SD, 1.26 +/- 0.14 micrograms 5HT/mg protein; 81% vs. controls) had significantly higher (P less than 0.001) natural killer (NK) activity (mean +/- SD, 9.1 +/- 3.9%) than control rats with average PSL (1.57 +/- 0.18 micrograms 5HT/mg protein). On the contrary, rats with constitutionally high PSL (2.42 +/- 0.21 micrograms 5HT/mg protein, 154% vs. controls) had somewhat lower (P less than 0.02) NK activity (4.1 +/- 1.7%) than control animals (5.7 +/- 1.9%). Antibody-dependent cellular cytotoxicity (ADCC) against nucleated targets of the RCH line, detecting lymphoid effectors, as well as ADCC against chicken red blood cells (CRBC), detecting predominantly non-lymphoid effectors, were also significantly higher (P less than 0.001) in rats with low PSL (19.6 +/- 6.8% vs. 6.6 +/- 3.1% in controls for lymphoid effectors, and 71.8 +/- 6.1% vs. 48.7 +/- 8.8% in control rats for non-lymphoid effectors). However, no significant alteration of either ADCC was determined in rats with high PSL. The results suggest in vivo regulation of natural cytotoxicity by serotonin.