Background: The heat shock protein H11 is silenced in melanoma cell lines, where its forced expression by demethylation with Aza-C triggers apoptosis. Objective: To examine whether H11 is silenced by aberrant DNA methylation in melanoma as compared to nevi and normal skin tissues. Methods: Cell suspensions from benign intradermal nevi, atypical nevi and malignant melanoma tissues were used in reverse-transcriptase PCR and methylation-specific PCR. Paraffin-embedded tissues were stained with H11 antibody. Results: H11 is methylated in 60–75% of melanoma and atypical nevi, but not in normal skin or most benign nevi. Methylation is inversely correlated with H11 expression. Conclusion: The heat shock protein H11 is silenced by aberrant DNA methylation in melanoma, but not benign melanocytic lesions or normal skin melanocytes. The data suggest that H11 is a promising target for the molecular therapy of melanoma.