A detailed case-control study was carried out on 24 PUVA-treated patients with squamous cell cancer of the skin, and on an accurately matched control population of 96 PUVA-treated patients. Possible co-carcinogens, such as prior therapy with tar, ultraviolet-B, ionizing radiation, methotrexate and arsenic, were investigated. The only statistically significant association to emerge was that of prior therapy with methotrexate: relative risk 3.5; 95% confidence interval 1.2-9.9. Our data suggest that prior therapy with methotrexate might be a risk factor for skin cancer in PUVA-treated patients.