Genistein inhibited topoisomerase II and I; it increased the enzyme-DNA complex in L1210 cells at 1 micrograms/ml, and interfered with pBR322 DNA relaxation by the enzymes. To test the role of topoisomerase in the transformation by oncogenes, the effect of genistein on the transformation of NIH 3T3 cells by transfection with [Val 12]Ha-ras was compared with that of N-alpha-tosyl-L-lysyl-chloromethyl ketone (TLCK), since genistein inhibits tyrosine kinase as well as TLCK. Genistein reduced the number of foci of the transformed cells, and suppressed selectively the growth of ras-transformed NIH 3T3 cells but not normal NIH 3T3 cells. In contrast, TLCK did not affect the transformation. It inhibited the growth of the normal cells but not the transformed cells.