During the last few years, the incidence and mortality of human melanoma have rapidly increased. Metastatic spread of malignant melanoma is often associated with cancer progression with poor prognosis and survival. These processes are controlled by dynamic interactions between tumor melanocytes and neighboring stromal cells, whose deregulation leads to the acquisition of cell proliferation capabilities and invasiveness. It is increasingly clear that a key role in carcinogenesis is played by secreted molecules either by tumor and surrounding stromal cells. To address the issue of the proteins secreted during cancer progression, the proteomic profiling of secretomes of cancer cell lines from different melanoma metastases of the same patient (PE-MEL-41, PE-MEL-47, and PE-MEL-43) was performed by applying a shotgun LC-MS/MS-based approach. The results provide a list of candidate proteins associated with the metastatic potential of PE-MEL melanoma cell lines. Among them, several matricellular proteins previously reported as involved in melanoma aggressiveness were identified (i.e., SPARC, osteopontin). In addition, the extracellular matrix protein 1 that stimulates proliferation and angiogenesis of endothelial cells as well as the fibronectin, involved in cell adhesion and motility, were identified. The present work provides the basis to clarify the complex extracellular protein networks implicated in human melanoma cell invasion, migration, and motility.