The effect of substituting a methyl group at the non-benzo 'bay-region' site of several polycyclic aromatic hydrocarbons on skin tumor-initiating activity was determined. A methyl group at this position enhanced the tumor-initiating activity of dibenz[a,h]anthracene, 3-methylcholanthrene and 7-methyldibenz[a,j]anthracene, but not of dibenz[a,c]anthracene. 2,3,7,8-Tetrachlorodibenzo-p-dioxin was an effective inhibitor of skin tumor initiation by 7,14-dimethyldibenz-[a,h]anthracene and 3,6-dimethylcholanthrene. There appears to be a general rule regarding methyl-substituted hydrocarbons: where a 'bay-region' exists in a polycyclic aromatic hydrocarbon molecule, methyl-substitution at the non-benzo 'bay-region' site results in enhanced tumor-initiating activity. The effect of methyl substitution in this position can be most simply explained as due to enhancement of the reactivity of the benzo ring through distortion of the aromatic ring system from planarity. The consequences of this effect are discussed.