Bovine milk lactoferrin (2 to 20 mu g ml(-1)) changed enhancement of [H-3]thymidine incorporation by phytohemagglutinin-stimulated rat spleen lymphocytes into suppression as their lactoferrin-withdrawal incorporation increased to greater than 10 000 cpm culture(-1) under the present isotope-labeling conditions. The enhancement disappeared by 15-min delayed addition of lactoferrin after addition of lectin. There was no lactoferrin effect when the cells were stimulated with 12-O-tetradecanoylphorbol-13-acetate plus ionomycin. Thus, lactoferrin has a certain extracellular effect on lymphocyte proliferation in response to the lectin.