Wolbachia are maternally inherited endosymbionts that infect nearly half of all arthropod species. Wolbachia manipulate their hosts to maximize their transmission, but they can also provide benefits such as nutrients and resistance against viruses to their hosts. The Wolbachia strain wMel was recently found to increase locomotor activities and possibly trigger cytoplasmic incompatibility in the transinfected fly Drosophila nigrosparsa. Here, we investigated, in females of both D. melanogaster and D. nigrosparsa, the gene expression between animals uninfected and infected with wMel, using RNA sequencing to see if the two Drosophila species respond to the infection in the same or different ways. A total of 2164 orthologous genes were used. The two fly species responded to the infection in different ways. Significant changes shared by the fly species belong to the expression of genes involved in processes such as oxidation-reduction process, iron-ion binding, and voltage-gated potassium-channel activity. We discuss our findings also in the light of how Wolbachia survive within both the native and the novel host.