Xeroderma pigmentosum group A gene-deficient mice easily develop skin cancers by ultraviolet radiation. Natural killer cells play an important part in tumor surveillance. To study whether ultraviolet radiation-induced suppression of natural killer cell function is involved in the high incidence of skin tumors in patients with xeroderma pigmentosum, we analyzed the number and activity of natural killer cells in ultraviolet B-irradiated xeroderma pigmentosum A model mice. The number of natural killer cells in peripheral blood significantly decreased after ultraviolet B-irradiation only in xeroderma pigmentosum A mice, but those in the spleen were not affected. As compared with the wild-type mice, the xeroderma pigmentosum A mice displayed a higher level of spontaneous splenic natural killer cell activity (10%-15% vs 3%) and inducible natural killer activity (30%-50% vs 20%-25%) after injection of polyinosinic:polycytidylic acid. At 24 h after the last irradiation of three and five daily consecutive exposures to 500 mJ per cm2-ultraviolet B, however, the natural killer activity in xeroderma pigmentosum A mice decreased to 60 and 30% of the preirradiated level, respectively, but it did not in the wild-type mice. The depression of natural killer activity in xeroderma pigmentosum A mice recovered to a normal level at 10 and 15 d after the last irradiation, respectively. The high incidence of skin cancers in xeroderma pigmentosum patients may be mainly due to a defect in the repair of ultraviolet-damaged DNA of cutaneous cells, and possibly also due to an intensified ultraviolet-induced immunosuppression. Moreover, the present study suggests that the enhanced ultraviolet-induced impairment of natural killer function could be partially involved in cancer development.