Overexpression of cyclooxygenase-2 (COX-2), characterizes tumors with high potential for local invasion and lymph node involvement. We investigated the expression of COX-2 in primary tumors and metastatic regional lymph nodes (TDL) from untreated and chemotherapy treated cervical cancer, as well as vulvar cancer. Immunostaining of COX-2, expressed as values of COX-2 intensity density (COX-2 IDV) was performed on 57 metastatic TDL and 24 corresponding primary rumors from 14 cervical and 9 vulvar cancer patients admitted to the Department of Obstetrics and Gynecology, Catholic University of Rome. In 6 locally advanced cervical cancer tissue samples, from both primary tumor and TDL, were obtained after chemotherapy treatment. In untreated cervical cancer, COX-2 IDV in tumor cells from positive TDL were significantly lower (median 0.69, range 0.22-0.92) than those from primary tumors (median = 3.84, range 0.19-7.67) (p=0.011). In cervical cancer exposed to chemotherapy, COX-2 IDV in tumor cells from positive TDL were significantly lower (median = 2.06, range 1.48-6.52) than those from primary tumors (median = 6.4, range 4.5-13.7) (p=0.037). In vulvar cancer COX-2 IDV in tumor cells from positive TDL were lower (median = 0.39, range 0.02-6.09) than those from primary tumors (median = 2.49, range 0.71-8.10) (p=0.04). In conclusion, we showed that COX-2 expression is down-regulated in cervical and vulvar tumor cells invading the regional lymph nodes with respect to primary tumors, thus emphasizing the need for deeper insight into the tissue specific relation between tumor cells and node microenvironment.