Systematic crosses between various strains of Drosophila melanogaster lead in some cases to partly sterile F1 females (SF females). Two main classes of strain, inducer and reactive, have been denned on the basis of this sterility, which shows very specific physiological features. SF females arise only when reactive females are crossed with inducer males. In contrast, F1 females (RSF) produced by the reciprocal cross between inducer females and reactive males have normal fertility. All wild populations tested are of the inducer category, laboratory strains are either inducer or reactive. Sterility is the result of interaction between two genetic factors denoted I and R, respectively responsible for the inducer and reactive conditions and whose unusual genetic behaviour has been described in other papers. The present paper reports experiments showing that the I–R interaction is also responsible for high levels of X nondisjunction and of mutation in the SF female germ-line. The analogy with the P-M system of Kidwell, Kidwell & Sved (1977b), is discussed as are also the implications of the existence of the I-R system for spontaneous mutation research in D. melanogaster.