The extent of PTEN loss that confers clinical and biological impact in melanoma is unclear. We evaluated the clinical and biologic relevance of PTEN dosage in melanoma and tested the postulate that partial PTEN loss is due to epigenetic mechanisms. PTEN expression was assessed by immunohistochemistry in a stage III melanoma cohort (n = 190) with prospective follow up. Overall, 21 of 190 (11%) tumors had strong PTEN expression, 51 of 190 (27%) had intermediate PTEN, 44 of 190 (23%) had weak PTEN, and 74 of 190 (39%) had absent PTEN. Both weak and absent PTEN expression predicted shorter survival in multivariate analyses (hazard ratio = 2.13, P < 0.01). We show a continuous negative correlation between PTEN and activated Akt in melanoma cells with titrated PTEN expression and in two additional independent tumor datasets. PTEN genomic alterations (deletion, mutation), promoter methylation, and protein destabilization did not fully explain PTEN loss in melanoma, whereas PTEN levels increased with treatment of melanoma cells with the histone deacetylase inhibitor LBH589. Our data indicate that partial PTEN loss is due to modifiable epigenetic mechanisms and drives Akt activation and worse prognosis, suggesting a potential approach to improve the clinical outcome for a subset of patients with advanced melanoma.