Background: The AKR family 1 member C3 (AKR1C3) was known to act as antioxidant and indirectly govern ligand access to various receptors and regulate the trans-activational activities of these nuclear receptors. Deregulated expression of AKR1C3 has been reported in multiple types of cancers. But there is no report on the expression of AKR1C3 in melanoma. Objectives: To figure out expression level of AKR1C3 in vivo and relation between sodium butyrate (NaBu) and AKR1C3 in vitro in melanoma. Methods: We investigated the expression levels of AKR1C3 in 6 human cutaneous melanoma tissues and 10 normal skin tissues by immunohistochemical staining and western blotting, while measuring expression levels of AKR1C3 in human melanoma cell G361, SK-MEL24 and human cervical cancer cell Hela, following NaBu treatment. Results: The results showed the downregulation of AKR1C3 in melanoma. Also we found decreased expression of AKR1C3 in human melanoma cell G361. Histone modification is known to be an essential regulatory mechanism associated with various genetic processes. Here we demonstrated upregulation of AKR1C3 in G361 cells following treatment with NaBu known as HDAC inhibitor. Conclusion: Our results showed that downregulation of AKR1C3 expression may be associated with melanoma development. We also demonstrated that inhibition of histone deacetylation following NaBu treatment increased AKR1C3 expression in melanoma cells. But further studies are needed to know the exact role of AKR1C3 in melanoma.