The cross of Drosophila melanogaster females to Drosophila simulans males produces lethal F1 hybrid males. These lethal phenotypes can be suppressed by mutations in the D. melanogaster gene Hybrid male rescue (Hmr), demonstrating that Hmr has a major role in causing lethality in this hybridization. We performed parallel crosses to generate viable (Hmr-) and lethal (Hmr+) hybrid male larvae and used microarrays to compare whole-genome transcriptional profiles between these two samples. This comparison was done to investigate two questions: whether hybrid lethality is associated with substantial gene misregulation, and whether a mechanistic basis for hybrid lethality can be inferred from the identities of differentially expressed individual transcripts. We report that a surprisingly small number of genes have a significant difference in transcript abundance between lethal and viable hybrid males. There is a significant over-representation of genes encoding proteosome subunits among those upregulated in lethal hybrids relative to viable hybrids. Genetic tests, however, failed to fully support the hypothesis that this overexpression is causing hybrid lethality. Hybrid females were previously reported to have a significantly different expression pattern of sex-biased genes compared to the parental species. We find no such differences between lethal and viable hybrid males. We did find a significant deficit of X chromosome genes among those downregulated in lethal hybrids, but not among those upregulated. We suggest that while interspecific hybrids may have substantial amounts of gene misregulation compared to their parental species, many of these transcriptional differences may be only indirectly related to hybrid incompatibility phenotypes.