Psoriasis, an inflammatory autoimmune disease, is characterized by increased level and activity of the proinflammatory cytokine TNF-alpha in affected lesions. Two promoter region polymorphisms of the TNF-alpha locus--one at position -308 and the other at -238--were examined in 99 Caucasian patients (64 with type I and 35 with type II psoriasis) and in 123 controls. A highly significant difference in the distribution of the -238 polymorphism--the TNF (G,A) genotypes--was detected between the type I psoriasis patients and controls: compared to the controls, the frequency of the homozygous TNF-G genotype was decreased (55 vs. 91%; p = 0.0000000274; corrected p = 0.0000001644; odds ratio = 0.12), whereas that of TNF-G,A heterozygotes was increased (41 vs. 8%; p = 0.000000264; corrected p = 0.000001584; odds ratio = 7.73) in patients. No significant differences were observed in the distribution of the TNF-A homozygotes. These results suggest that homozygosity of the G allele is associated with a lower relative risk (resistance), whereas heterozygosity at this locus is associated with an increased risk (susceptibility) of type I psoriasis.