The hypermelanosis on the blind-side of Cynoglossus semilaevis have reduced its market value and affected its availability in the enhancement program, which has adverse effects on the sustainable development of the farming industry. However the underlying mechanisms of hypermelanosis have not been clarified yet. To investigate the cytological mechanism of hypermelanosis on the blind-side of C. semilaevis, we identified three kinds of chromatophores, namely melanophore, xanthophore and iridophore, based on the microscopic observation, and we described their morphology. The melanophore contained black and brown pigment granules and had a relatively larger nucleus. They could be characterized into two types according to the morphology. In contrast, the nuclei of xanthophore and iridophore were relatively small. The distribution and pattern of the three chromatophores in the eye-side and the blind-side skin were examined and compared. We isolated and sequenced the proopiomelanocortin (POMC) cDNA from pituitary using RT-PCR and RACE. The POMC cDNA was 910 bp in length consisting of a 114 bp 5'-UTR, a 154 bp 3'-UTR, and a 642 bp open reading frame that encoded 213 amino acids. The amino acid sequence was composed of the signal peptide, ACTH, α-MSH, βMSH, γ-LPH, and β-endorphin domains, without γ-MSH and most of the joining peptide domains. The amino acid homology analysis revealed that C. semilaevis POMC shared 30%−64% similarity with their fish counterparts. Quantitative PCR results showed that POMC mRNA was mainly expressed in the pituitary and was also expressed in the brain, gonad and the black skin (hypermelanosis) on the blind side. The POMC mRNA expression level in the blind-side black skin was significantly higher than that in the ocular-side and in the blind-side normal skin, which indicated a close correlation between the POMC gene and the hyperpigmentation on the blind-side. Our study provided basic information on the cytological and molecular mechanisms of hyperpigmentation on the blind-side of C. semilaevis.