To examine the effects of chronic ultraviolet light on human epidermal cells, we grafted white human skin onto recombinase activating gene-1 knockout mice. We found previously that the maximal concentration of ultraviolet B radiation (290-320 nm) tolerated by human skin xenografts was 500 J per m2 when given three times weekly. One hundred and fifty-eight grafted mice were randomized and observed for a median of 10 mo in four groups: (i) no treatment; (ii) one treatment with the chemical carcinogen dimethyl-(a)benzanthracene; (iii) ultraviolet B three times weekly; and (iv) a combination of dimethyl-(a)benzanthracene and ultraviolet B. Approximately half of the skin specimens treated with ultraviolet B developed superficial milia and epidermal cysts. Grafts contained up to seven milia lesions between 4 and 8 mo after initiation of treatment, whereas the number of larger epidermal cysts was rarely more than two. Milia and cysts developed in the skin regardless of pigmentation or tanning. Actinic keratoses arose in 9% of grafts treated with ultraviolet B alone and in 19% of grafts treated with the combination of dimethyl-(a)benzanthracene and ultraviolet B. Invasive squamous cell carcinomas developed in 10% of grafts after combined dimethyl-(a)benzanthracene and ultraviolet B treatment and lesions were restricted to skin grafts that did not tan. These findings demonstrate that (i) development of ultraviolet-induced lesions can be experimentally accelerated in human skin, (ii) xenografted recombinase activating gene-1 deficient mice are superior to severe combined immunodeficiency disease mice for chronic ultraviolet B studies, and (iii) benign cystic tumors and squamous cell carcinomas are caused by ultraviolet B.