The abilities of various mono and dimethyl derivatives of benzo(a)pyrene (BP) to initiate skin tumors in mice were determined by using a two-stage system of tumorigenesis. 11 -Methylbenzo(a)pyrene was found to be approximately 3 times more active as a tumor initiator than was the parent hydrocarbon; 1 - methyl benzo(a)pyrene was about twice as active as was BP. Substitution of a methyl group in positions 7, 8, 9, or 10 of BP, which would be involved in a bay-region diol-epoxide, completely counteracts the tumor-initiating ability of BP. 3-, 4-, and 12-methyl-benzo(a)pyrenes had activity equivalent to that of BP, whereas 2-, 5-, and 6-methylbenzo(a)pyrenes, as well as 1,2-, 4,5-, 1,6-, and 3,6-dimethylbenzo(a)pyrenes, were all less active than BP. The concepts of steric inhibition of metabolic activation and stereospecific activation are suggested to explain the tumor-initiating activities of various methylated derivatives. © 1980, American Association for Cancer Research. All rights reserved.