ABSTRACT The inheritance of susceptibility to audiogenic seizures (ASS) was studied in the C57BW6J (B6) and DBA/2j (D2) progenitor strains, their reciprocal F1 hybrids, backcross generations and in 21 B6 × D2 recombinant inbred (RI) strams of mice at 21 days of age. All of the D2 mice tested experienced ASS, whereas none of the B6 mice responded to the sound. Although 23% of the F1 mice experienced wild running, they were generally as resistant to ASS as their B6 parents. Mice of the F1 × B6 backcross generation were also resistant to ASS. In the F1 × D2 backcross generation, however, a significant pre-ponderance (72%) of AS-susceptible mice was found. No significant association was observed between any of the four coat-color phenotypes that were segregating in this generation and susceptibility to ASS. A continuous distribution of mean seizure severity scores and several new audiogenic response phenotypes, distinctly different from the phenotypes of either progenitor strain, were found among the 21 RI strains. These and the results from the F1 × D2 backcross generation suggest that the difference in AS susceptibility between 21-day-old B6 and D2 mice cannot be under the control of a single locus. In addition, no association was found between AS susceptibility and the chromosome 4 markers Lyb-2, Mup-1 and b among the 21 RI strains. An association was observed, however, between AS susceptibility and the Ah locus. Several of the RI strains that were AS resistant at 21 days of age became AS susceptible as adults. One RI strain was susceptible to ASS at both young and adult ages. The B6, D2 and F, mice were completely resistant to ASS at adult ages. Genetic differences were found among the RI strains for the incidence, onset, duration, and type of severity of ASS. A remarkable amount of phenotypic variability in the audiogenic response, which can be attributed only to the influence of environmental factors, occurred within several of the RI strains. A multiple-factor mode of inheritance involving a physiological threshold can account for our observations.