A microassay for DNA methylase is described which can detect activity in as few as 50 tissue culture cells. The cells are lysed and incubated for 2 h at 37 degrees C with 3 microCi high specific activity [3H]AdoMet and 0.5 microgram poly[d(I-C).d(I-C)] in a volume of 23 microliters. Ribonuclease is present during the assay and the product DNA is isolated by phenol extraction after protease digestion.