In young adults and children, spitzoid melanoma carries striking resemblance to spitz nevus clinically and histopathologically. Many have attempted to differentiate between these 2 entities by searching for immunohistochemical and molecular diagnostic differences. Here, the authors report a spitzoid melanoma in a young adult, which was morphologically similar to a spitzoid nevus and carried a loss of chromosome 9 detected by an array-based comparative genomic hybridization. However, the expression of cyclin-dependent kinase inhibitor 2A (p16) protein, encoded on chromosome 9p21, detected by the immunohistochemical study was heterogeneous among tumor cells. This case demonstrates the presence of clonal heterogeneity of losses of chromosome 9 and p16 protein expression within a single spitzoid melanoma, challenging a robust application of p16 expression detected only by immunohistochemical staining in determining the diagnosis of spitzoid melanoma.