Sodalis glossinidius, one of the three tsetse fly maternally inherited symbionts, was previously shown to favor fly infection by trypanosomes, the parasites causing human sleeping sickness. Among a population of flies taking a trypanosome-infected blood meal, only a few individuals will acquire the parasite; the others will escape infection and be considered as refractory to trypanosome infection. The aim of the work was to investigate whether fly refractoriness could be associated with specific Sodalis gene expression. The transcriptome of S. glossinidius harbored by flies that were fed either with a non-infected blood meal (control) or with a trypanosome-infected meal but that did not develop infection were analyzed, using microarray technology, and compared. The analysis using the microarray procedure yielded 17 genes that were found to have a significant differential expression between the two groups. Interestingly, all these genes were overexpressed in self-cured (refractory) flies. Further analysis of functional annotation of these genes indicated that most associated biological process terms were related to metabolic and biosynthetic processes as well as to oxido-reduction mechanisms. These results evidence the occurrence of molecular crosstalk between the different partners, induced by the passage of the trypanosomes through the fly's gut even though the parasites were unable to establish in the gut and to develop a permanent infection.