The food mutagen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) is an analogue of quinoline, a hepatocarcinogen. 2-Aminofluorene, benzidine and 3,2'-dimethyl-4-aminobiphenyl (DMAB) are potent inducers of unscheduled DNA repair in primary culture rat liver hepatocytes, as was IQ (151 grains/nucleus at 1 X 10(-6) M). Quinoline, on the other hand, is only weakly positive in this assay (15 grains/nucleus at 1 X 10(-3) M). IQ, quinoline and DMAB were applied topically to shaved skin of Sencar mice with promotion by 12-O-tetradecanoylphorbol 13-acetate (TPA) for 20 weeks, when 14 of 20 mice in the quinoline group had 25 tumors, but only one of 30 animals in the IQ group and five of 30 in the DMAB group were tumor-bearing. Analogs of IQ synthesized by substitution at the 2- or 3-position with amino or methyl groups were assayed with the Ames Salmonella typhimurium tester strains TA98 and TA100. Mutagenicity for TA98 is reduced in the absence of the 3-methyl group and is completely abolished with removal of the 2-amino moiety. None of these analogs are strong mutagens for TA100. Exocyclic N-oxidation is a likely obligatory step in the activation of IQ to a mutagen.