Melanoma is the least common but most serious form of skin cancer. The leading cause of death in melanoma patients is widespread metastasis caused by increased cell motility and a rich blood supply for tumor cells. A unique form of microcirculation called vasculogenic mimicry, which efficiently supplies blood to tumor cells, has been reported recently. Apoptosis-related protein performs a nonapoptotic function to promote migration and invasion of tumor cells. This study focuses on the nonapoptotic role of caspase-3 in melanoma and its effects on the migration, invasion, and vasculogenic mimicry formation of melanoma cells. Human melanoma samples were used to detect active caspase-3 expression and determine its relationship with clinicopathologic parameters. In addition, a human melanoma A375 cell line was used to determine the role of caspase-3 in migration and invasion using z-DEVD-fmk, a selective caspase-3 inhibitor, to inhibit caspase-3 activity. The findings suggest that active caspase-3 is expressed in nonapoptotic melanoma cells and is related to metastasis and vasculogenic mimicry formation in patients with melanoma. Low doses of caspase-3 inhibitor reduced caspase-3 activity without affecting cell apoptosis. Inhibition of caspase-3 activity using low-dose z-DEVD-fmk decreased the migration, invasion, and vasculogenic mimicry formation of melanoma cells in vitro. Similarly, downregulation of caspase-3 by specific small interfering RNA also inhibited the migratory, invasive, and tube-forming potential of melanoma cells. The caspase-3-mediated promotion of melanoma cell motility may be because of the cleavage of matrix metalloproteinase-2.