The study of hybrid inviability reveals cryptic divergence between the genetic interactions that maintain stable phenotypes in the pure species. We characterized the effects of natural variation on the penetrance of hybrid inviability phenotypes in crosses between Drosophila melanogaster and two species of the D. simulans subcomplex, D. simulans and D. sechellia. Using a panel of wild-caught lines, we studied the levels of genetic variance present in D. simulans and D. sechellia affecting prezygotic and post-zygotic isolation in hybridizations with D. melanogaster females. We observed extensive variability in the viability of hybrid individuals, dependent on the genotype of the parents, suggesting that intraspecific natural variation manifests directly in hybrid phenotypes. Furthermore, we found that genetic background significantly affects the penetrance of a well-studied determinant of hybrid inviability: the interaction between Hmrmel–Lhrsim. Our results suggest that hybrid inviability – and reproductive isolation generally – can be modified by polymorphisms at multiple loci segregating within the parental species. Just as the penetrance of most mutant phenotypes can be modified by the genetic background within the pure species, the penetrance of hybrid inviability phenotypes is highly influenced by the parental genotypes.