Oral melanomas have some histopathological resemblance with its cutaneous counterpart; however, an aggressive behavior is more common in tumors that occur in the oral cavity. Several markers have been suggested as indicative of tumoral progression and aggressiveness, such as cyclooxygenase 2 (COX-2) and Ki67. In this study, we have compared the expression of COX-2 and Ki67 in a series of amelanotic (n=7) and melanotic oral melanomas (n=22). The cases were selected from 4 pathology laboratories and submitted to the immunohistochemical (IHC) reactions. We analyzed the IHC staining based on a qualitative ? using visual scores; and a computer-assisted method (quantitative) using scanned slides and software for digital analysis. COX-2 was expressed in all oral melanomas; however, its intensity was significantly higher in the amelanotic ones (P<0.001). Similarly, a high Ki67-positivity index was observed in the amelanotic than melanotic ones (P<0.001). Based on these results, we suggest that amelanotic oral melanomas have marked pro-inflammatory and high-proliferative phenotype, justifying their more aggressive behavior compared with the melanotic ones.