Keratinocyte overgrowth after UVB exposure is believed to contribute to skin photoageing and cancer development. However, little is known about the transcription factors that epigenetically regulate keratinocyte response to UVB. Recently, HIF-1alpha was found to play a role in epidermal homeostasis by controlling the keratinocyte cell cycle, and thus, we hypothesized that HIF-1alpha is involved in UVB-induced keratinocyte growth. In cultured keratinocytes, HIF-1alpha was found to be down-regulated shortly after UVB exposure and to be involved in UVB-induced proliferation. In mice repeatedly treated with UVB, the epidermis became hyperplasic and keratinocytes lacked HIF-1alpha in nuclei. Based on these results, we suggest that the deregulation of HIF-1alpha is associated with UVB-induced hyperplasia of the epidermis. This work provides insight of the molecular mechanism underlying UV-induced photoageing and skin cancer development.