The transcription factor activating transcription factor 2 (ATF2) has been shown to be associated with melanocytic oncogenesis and melanoma tumor proliferation in preclinical models. The clinical significance of ATF2 expression is unknown. To determine the prognostic value of ATF2 in melanoma, we evaluated the pattern and level of ATF2 expression in a large cohort of melanoma specimens. Immunohistochemical staining was performed on a tissue microarray representing 544 patients with a mean follow-up time of 60 months. Expression was evaluated semiquantitatively and correlated with overall survival and other clinicopathological data. Strong cytoplasmic ATF2 expression was associated with primary specimens rather than metastases (P < 0.0001) and with better survival (P = 0.0003). Strong nuclear ATF2 expression was associated with metastatic specimens (P < 0.0001) and with poor survival (P = 0.0008). Patients who had both weak cytoplasmic and strong nuclear ATF2 staining had the worst outcome, both among the full cohort of patients (P < 0.0001) and among the patients with localized disease (n = 269; P < 0.0001). On multivariate analysis of the primary cutaneous specimens, weak cytoplasmic staining and strong nuclear staining was an independent predictor of poor outcome, as was Clark level. Nuclear ATF2 is likely to be transcriptionally active, whereas cytoplasmic ATF2 probably represents an inactive form. These findings support other preclinical findings in which transcriptionally active ATF2 is involved in tumor progression-proliferation in melanoma. Moreover, our findings suggest that ATF2 might be a useful prognostic marker in early-stage melanoma.