The relationship of ovostatin 2 (OVOS2) expression with the clinicopathological features of cutaneous malignant melanoma (CMM) was investigated to identify OVOS2 expression in cutaneous melanocytic lesions, and to reveal whether OVOS2 has a function in melanoma progression. Eight specimens of CMM and paracancerous tissue were analyzed using real-time polymerase chain reaction (PCR) and western blot for the mRNA and protein expression of OVOS2, respectively. Immunohistochemical staining was performed on 52 CMM and 62 nevi, followed by clinicopathological significance analysis. The proliferative cells were visualized by staining with Ki-67 antibody. The intensity of angiogenesis was assessed by staining with vascular endothelial growth factor (VEGF). Real-time PCR and western blot analyses showed that OVOS2 was significantly upregulated in cutaneous melanoma than in paired normal skins. Immunohistochemistry showed that 86.5% (45/52) of malignant cases showed OVOS2 cytoplasmic expression compared with 29% (18/62) in benign nevi. OVOS2 expression was significantly higher in invasive and metastatic melanoma than in in situ melanoma (P < 0.01). Furthermore, OVOS2 expression was positively correlated with the known prognostic variables of melanoma including clinical stage, Clark level and Breslow depth. It was also significantly associated with ulcer status, Ki-67 labeling index and VEGF expression in primary melanoma. OVOS2 expression was significantly increased in CMM, which increased incrementally from benign nevi to melanoma and appeared to be involved in the progression of melanoma.