Ultraviolet irradiation stimulates keratinocytes and dermal fibroblasts to release cytokines involved in apoptosis and immunomodulation, such as tumor necrosis factor-alpha and interleukin-1alpha. Recent work has associated the -308A polymorphism of the human tumor necrosis factor-alpha promoter with systemic lupus erythematosus and adverse outcomes in several infectious diseases. To explore the role of this polymorphism in ultraviolet-induced disease, we used two approaches. First, we examined its prevalence in individuals with different ultraviolet sensitivity. Compared with healthy controls, there was a substantially increased prevalence of -308A in subacute cutaneous lupus erythematosus, an extremely photosensitive form of cutaneous lupus erythematosus, but not in discoid lupus erythematosus, a less photosensitive form. Next, to examine molecular regulation by tumor necrosis factor -308A, cultured 3T3 fibroblasts were transiently transfected with chloramphenicol acetyl transferase reporter constructs under the control of either -308A or the wild-type -308G promoter. Without added interleukin-1alpha the two constructs produced similar baseline chloramphenicol acetyl transferase activity and similar responses to ultraviolet. The responses to interleukin-1alpha, a photoinduced cytokine, were markedly different: interleukin-1alpha without ultraviolet produced a 15-fold increase in chloramphenicol acetyl transferase transcription from the -308A construct without affecting the wild-type -308G. Interleukin-1alpha plus ultraviolet B caused a remarkable 300-fold increase in -308A chloramphenicol acetyl transferase transcription over baseline, while increasing the wild type to <15% of this level. These results indicate a clear difference between the two promoters, including a striking synergy between ultraviolet B and added interleukin-1alpha in the induction of transcription by the tumor necrosis factor-alpha -308A promoter. Overall, our findings indicate a strong linkage between the -308A polymorphism and subacute systemic lupus erythematosus, which is likely to directly contribute to the photosensitivity of these patients.