Erythema nodosum is a common skin disease characterized by erythematous, tender subcutaneous nodules, mostly located on the lower extremities. Little is known about its pathogenesis, although a wide variety of aetiological factors (e.g. bacterial and viral infections, neoplastic diseases and drugs) have been described. Sarcoidosis, a typical granulomatous disease, often occurs in association with erythema nodosum (Loefgren syndrome). Since granulomatous diseases have been closely linked to a deregulated tumour necrosis factor (TNF)-alpha production, it was tempting to speculate whether TNF-alpha might play a role in the pathogenesis of erythema nodosum, at least in cases associated with sarcoidosis. A previously described nucleotide exchange, (G-A) at position -308 in the human TNF-alpha gene promoter, has been shown to be a major cause for enhanced TNF-alpha production. In the present report, we investigated the genomic TNF-alpha promoter region in patients suffering from EN with and without underlying sarcoidosis. Our results showed a strong correlation between the uncommon TNF A II allele and sarcoidosis-associated erythema nodosum. Patients with erythema nodosum without underlying sarcoidosis displayed a similar allele frequency compared with controls. Taken together, we provide evidence that erythema nodosum in association with sarcoidosis might be pathogenically linked to altered TNF-alpha production due to a genetic promoter polymorphism.