Light- and electron-microscopic analyses of chromosomal pairing and recombination in F1 and first-backcross generation mice of the C57BL/6J × Mus spretus cross revealed a variety of meiotic irregularities that could contribute to meiocyte loss and infertility. Pachytene anomalies included univalency, partially paired bivalents, homolog-length inequalities, nonhomologous pairing, and associations of asynapsed autosomal segments with the X chromosome. These phenomena were most prevalent in Fi males, which are invariably sterile. Although F[ females were qualitatively fertile, breeding data indicated significant reproductive impairment. Molecular analyses of X-linked and pseudoautosomal loci in sterile and fertile backcross males revealed that the failure of X-Y pairing and recombination is correlated with heterozygosity within the pseudoautosomal regions of the X and Y chromosomes. In addition to impairing fertility, the synaptic disturbances (such as localized asynapsis and nonhomologous pairing) observed in F1 individuals can potentially alter recombinational patterns, thereby contributing to the genetic-map distortion observed with this interspecific cross. Together, the cytogenetic and reproductive data suggest that sex-related differences in the gametogenic process, quantitative differences in the incidence of synaptic irregularities in female and male meiosis, and phenomena associated with the X and Y chromosomes comprise the etiological basis of the sex-biased F1 sterility. The differential gender-related effects of these cytogenetic phenomena may constitute the underlying basis of Haldane’s rule in mammals.