Cassava bacterial blight caused by Xanthomonas phaseoli p.v manihotis (Xpm) is a common disease of cassava (Manihot esculenta). The molecular mechanisms underlying susceptible and resistant response and host defense mechanisms are currently unknown. In this study, we performed large-scale mRNA expression profiling using an RNAseq approach to identify Cassava responses in MBRA685 variety inoculated with Xpm618 (resistant response) and Xpm318 (susceptible response) strains. Bioinformatic analysis revealed significantly differentially expressed genes (DEGs) by Xpm681 in MBRA685 with higher fold change values. Unique prevalent GO categories for Xpm681 response included “protein kinase activity” and “phosphorylation”; “amino acid biosynthetic process” for Xpm318 response and “regulation of transcription” and “transcription factor activity” in both responses. There were particular differences between the cultivars in the intensity of expression of genes with putative roles in transcriptional activity, receptor and signaling processes, secondary metabolism and photosynthesis. The differences between two interactions can be explained quantitatively, the resistant response was weaker than the susceptible response. Quantitative real-time PCR experiments confirmed the reliability of our RNAseq data.