Excessive ultraviolet B (UVB) irradiation causes apoptotic cell death or induction of tumors in skin. Melatonin is a promising antioxidant and direct radical scavenger. Recently, it was reported that melatonin increases the survival of ultraviolet-B (UVB)-irradiated HaCaT keratinocyte cell lines. However, the precise molecular mechanisms underlying protective effect of melatonin on UVB damage are largely unknown. In this study, to gain more insight into the molecular mechanisms involved in melatonin-induced cell survival on UVB-irradiated HaCaT keratinocytes, we performed cDNA microarray analysis. HaCaT keratinocytes were incubated without or with melatonin at 100 nm for 30 min prior to UVB irradiation at 100 mJ/cm(2), and total RNA was isolated. Our data showed that the expression of apoptosis regulator genes (apoptosis related protein-3, apoptotic chromatin condensation inducer in the nucleus), cancer related genes (tumor suppressor deleted in oral cancer-related 1), cell cycle regulator (cyclin-dependent kinase 2 interacting protein), enzymes (glutathione peroxidase 1, ubiquitin-conjugating enzyme E2M), and signal transducer genes [fibroblast growth factor (acidic) intracellular binding protein, transforming growth factor beta-stimulated protein TSC-22] were decreased by melatonin treatment in the UVB-irradiated HaCaT keratinocyte cell lines, compared to that of UVB-irradiated HaCaT cells without melatonin. Thus, findings of the present study demonstrate that melatonin modulates the expression of apoptosis related genes in UVB-irradiated HaCaT cells, resulting in increasing cell survival, thereby suggesting that melatonin may be used as a promising sunscreen substance to reduce cell death of keratinocytes after excessive UVB irradiation.