The in vitro effect of proguanil and its active metabolite cycloguanil on proliferating human blood mononuclear cells was studied. Proguanil had no effect on ¹⁴C-thymidine incorporation or on the number of cells. Cycloguanil, in concentrations corresponding to the plasma levels found in clinical practice, blocked the endogenous synthesis of thymidine and decreased the number of mitogen- and antigen-stimulated cells. The effect on phytohaemagglutinin-stimulated cells was transient. Higher concentrations of cycloguanil, corresponding to intralymphocytic levels in clinical practice, permanently suppressed the growth of lymphocytes. The effect of cycloguanil could be reversed by low doses of folinic acid and high doses of folic acid.