Abstract: Determining risk assessment for aggressive behavior of atypical Spitz tumors (ASTs) remains a significant challenge for pathologists. Despite the presence of many concerning histological features such as tumor ulceration, expansile growth, dermal mitotic rate, and cytological atypia, the overwhelming majority of these tumors behave in an indolent fashion. Recently, we have noted that using cytogenetics, one can identify ASTs with high likelihood for aggressive behavior allowing for a clinically significant risk assessment. In this retrospective case-controlled study, we examined the clinical and histological features of 24 cases of ASTs that were found to have isolated copy number deletions in 6q23 when studied by probes targeting 6p25, 6q23, Cep6, 11q13, 9p21, and Cep9. Although 6 of 11 patients had a positive sentinel node biopsy, none of the patients developed tumor in a nonsentinel node, palpable adenopathy, in transit metastasis, or distant metastasis. Histopathologically, the tumors showed minimal pagetoid spread (P = 0.004) and trended toward a histological presentation with expansile nodular growth (P = 0.08) and focal ulceration (P = 0.19). Furthermore, we also depict and illustrate the challenges that may occur in accurately identifying 6q23 deletions using fluorescence in situ hybridization in ASTs.