Abstract Two classes of inhibitors of histone methyltransferase I from calf thymus are reported. High concentrations ( ≧ 10 mM ) of various alkyl or aralkyl amines and polyamines were inhibitory to the enzyme. Spermine and spermidine were among the most potent compounds in this group. The best monoamine inhibitor was 2-phenylethylamine, which gave 47% inhibition at 10 m M. The substituted phenanthridinium compound ethidium bromide was also an inhibitor of the enzyme. A number of analogs of ethidium bromide were tested, and the most potent compound (17) gave 50% inhibition at 0.125 m M. S- Adenosyl- l- ethionine (SAM) showed competitive inhibition of the enzyme as determined from a Lineweaver-Burke plot, while ethidium bromide was noncompetitive.