Abstract: As a gonochoristic model animal, marine medaka (Oryzias melastigma) is good for studying the sex-specific responses of organisms to xenobiotic pollutants. We used comparative transcriptomics technology to systematically investigate the differentially expressed genes (DEGs) between the liver tissues of female and male medaka. We identified 683 significantly up-regulated DEGs in the females, and 668 DEGs in the males. The high expressed DEGs in the females were involved in the reproductive and sex hormone synthesis pathways, such as vitellogenin and estrogen receptor. The top twenty DEGs in the males were involved in energy metabolism, cytoskeleton and muscle contraction, such as pyruvate kinase, creatine kinase, myosin and troponin. Except for the DNA mismatch repair protein, all the 17 DEGs had similar magnitude and expression trends by both qRT-PCR and RNA-seq analyses, which confirms the reliability of the RNA-seq data. The results demonstrate that the gene expression patterns are different in the livers of female and male medaka, and the DEGs provide a theoretical basis for promoting the molecular mechanism of sex-specific responses of medaka to xenobiotic pollutants.