Conclusions The currently available genetic information on C. fluminea, an important freshwater clam, is very limited. In the present study, we report the transcriptome sequencing and de novo genetic analysis of this species using the Illumina GAIIx method. More than 62,250,336 high-quality reads were generated based on the raw data, and 134,684 unigenes with a mean length of 791 bp were assembled. This transcriptional information provides a more nuanced understanding of the underlying biological and physiological mechanisms that govern C. fluminea biology. To our knowledge, this is the first report of transcriptome sequencing in this species. In addition, the identification of 15 putative environmental pollution biomarkers, and the gene expression results following fluoxetine exposure are further expected to promote research on the use of C. fluminea in environmental toxicology. Data Deposition The Illumina GAIIx reads of C. fluminea were submitted to the NCBI Sequence Read Archive under accession number SRA062349.