Abstract Using deficiencies from Drosophila melanogaster, we looked for genomic regions in the sister species D. simulans that could cause lethality when hemizygous on a hybrid genetic background. Such genotypes allow hemizygous genes from one species to interact with heterozygous genes from other species and may correspond to the kinds of genotypes causing Haldane’s rule, the observation that if only one gender is sterile or inviable in species hybrids, it is nearly always the heterogametic sex. A survey of roughly 50% of the D. simulans genome (114 chromosome regions) revealed only four regions causing hybrid lethality and five causing severe reductions in hybrid viability. However, the viability of all of these genotypes was at least partially restored by rearing hybrids at lower temperature or using different genetic backgrounds from D. simulans. We therefore detected no D. simulans chromosome regions causing unconditional hybrid lethality, although several regions were shown to be deleterious under most tested temperatures and genetic backgrounds. The relative paucity of “inviability genes” supports the idea, suggested by work on other species, that hybrid inviability between closely related species might be caused by interactions among relatively few genes, while hybrid sterility may involve many more loci.