Tetraspanins (TSPANs) are transmembrane proteins which can interact with several molecules, such as integrins, immunoglobulins, and others TSPANs in order to create a network interaction called “TSPAN web”. TSPANs are involved in many physiological processes such as cell differentiation, proliferation, migration, invasion, signaling, and activation. The interactions mediated by integrins are important to cell-matrix adhesion, this process is commonly deregulated in cancer. Furthermore, aberrant expression of TSPANs has been associated with worst prognosis in several cancer types. However, their role in vulvar squamous cell carcinoma (VSCC) is still unknown. Thus, our aim was to evaluate two members of TSPAN family, CD63, and CD82, in VSCC. By qRT-PCR, we were able to access the gene expression profile of CD63 and CD82 in metastatic (SW962) and non-metastatic (SW954) vulvar cancer cell culture. Our results showed a high expression (Fold Change> 4) of CD63 in metastatic vulvar cells in comparison to non-metastatic cells. However, we found a decrease in the expression of CD82 in metastatic cells comparing to non-metastatic vulvar cells. The gene expression profiles of CD63 and CD82 seems to show an important role of CD63 as indicative of poor prognosis in vulvar cancers. CD82 expression profile corroborates with literature playing a role as a tumor suppressor. Furthermore, our preliminary results point these molecules as differential markers for prognosis in patients with VSCC. More studies are necessary for better understanding the role of these TSPANs in vulvar carcinoma.