Ultraviolet (UV) light is an epidemiological risk factor for melanoma, but its specific contribution to melanoma induction is not known. The first critical step of melanoma development, ie, the uncontrolled proliferation of melanocytes, may be induced by a combination of UV damage and an imbalance of growth factor production by cells in the immediate area of the melanocyte. Among several candidates, basic fibroblast growth factor (bFGF) is the major autocrine growth factor in melanoma and associated with tumor progression. Overexpression of bFGF via adenoviral gene transfer in human skin xenografted to severe combined immunodeficiency mice led to black-pigmented macules within 3 weeks of treatment. Immunofluorescence analysis demonstrated pathological hyperpigmentation, proliferation and hyperplasia of activated melanocytes, but no malignant transformation. Similar changes were observed in skin reconstructs. When bFGF was combined with UVB, pigmented lesions with hyperplastic melanocytic cells were detected, including a lesion with high-grade atypia resembling lentiginous forms of malignant melanoma. Donor-matched control grafts revealed no melanocytic changes. bFGF was overexpressed in dermal fibroblasts demonstrating the co-carcinogenic influence of paracrine-acting growth factors by cells of the microenvironment. This is the first report suggesting that an imbalance of physiological growth factor production in the skin may cause melanoma in combination with UVB.