Nephronectin (POEM) was originally identified as a factor involved in tissue morphogenesis. POEM has several characteristics of a matrix protein including an arg-gly-asp binding domain site that is recognized by integrins. Recently, deregulation of POEM was found in breast cancer. We therefore speculate that deregulation of POEM expression plays a role in the development or progression of malignant melanoma. Thus, we evaluated melanoma cell lines and tissue samples of malignant melanoma for POEM transcription. We found that POEM expression was reduced or lost in most cell lines and in all tumor samples analyzed. Reduced POEM expression occurred as early as in primary tumors detected by both immunohistochemical and reverse transcription-polymerase chain reaction analyses. Functional assays with stable POEM transfected cell lines revealed that POEM expression increased cell adhesion and decreased cell migration and invasion supporting a role of POEM in tumor progression. Interestingly, integrin alpha-8 expression, which was described as a receptor for POEM, is enhanced in malignant melanoma. Our studies thus indicate that loss of POEM expression may contribute to melanoma progression.