Tilapia (Oreochromis niloticus) cultures are frequently infected by Vibrio vulnificus, causing major economic losses to production units. Previously, tilapia expressing recombinant delta-5 desaturase and delta-6 desaturase (D56) were found to be resistant to V. vulnificus infection. In this report, we profile the D56-mediated molecular changes underlying this resistance in tilapia. A comparative transcriptome analysis was performed on V. vulnificus-infected wild-type and D56-transgenic tilapia using Illumina's sequencing-by-synthesis approach. Gene enrichment analysis on differentially expressed unigenes was performed, and the expression patterns were validated by real-time PCR.