Methionine has been successfully used to control tumor progression in vivo and to induce reversions of transformed cells in vitro. In the present study, we measured mutations at the HGPRT locus of RSV-transformed cells serially propagated in methionine-supplemented medium and assayed at each passage for thioguanine resistance. The frequency of spontaneous mutants at this locus was 7.2 X 10(-5); this value gradually increased during the methionine treatment to as much as 9.2 X 10(-4), and returned to initial values when the methionine treatment was withdrawn. It is proposed that the mutants were induced by the methionine derivative, S-adenosylmethionine, and the resulting mutant frequency determined by equilibrium between mutagenic action of this metabolite and DNA repair.