There is now increasing evidence that a constitutive expression of cyclooxygenase 2 (COX-2) plays a role in the development and progression of malignant ectodermal tumours. In this study, we investigated whether the selective inhibition of COX-2 would be beneficial in melanoma treatment. Nimesulide, a selective inhibitor of COX-2 that causes the breakdown of proinflammatory 2-series prostaglandins (PG2), adversely affected the growth of B16-F10 melanoma cells through the induction of differentiation. The intracellular levels of polyamine, as a proliferation marker, were reduced by the treatment; at the same time, transglutaminase activation and increase in melanin content, as differentiation indicators, were observed. The potential antimetastatic activity of the drug was further shown by means of the Boyden invasion assay and gelatin zymography for metalloproteinase activity. Comparable results were obtained after the treatment of cells with one of the 1-series PGs (PGE1). Therefore, our hypothesis is that the antineoplastic activity observed for nimesulide may be ascribed to intracellular changes in alterations in PG levels.