Several studies indicate that the immune system is stimulated in sudden infant death syndrome (SIDS). Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine that strongly affects the cytokine cascade. A genetic variant associated with high production of TNF-alpha may thus be of significance in the pathogenesis of SIDS. The purpose of the current study was to investigate possible relationships among the promoter polymorphisms -1031T/C, -857C/T, -308G/A, -244G/A, and -238G/A in the TNF-alpha gene and SIDS. The subjects investigated consisted of 148 SIDS cases, 56 borderline SIDS cases, 41 cases of infectious death, and 131 adult controls. When investigating each single nuclear polymorphism (SNP) separately, associations between -238GG and SIDS (p=0.022) and between -308GA and borderline SIDS (p=0.005) were found. There were no associations between any of the other SNPs investigated. Furthermore, a SNP profile was constructed by creating a genotype pattern from the investigated SNPs. Fifteen gene combinations were obtained, and 4 profiles had significantly different frequencies in SIDS cases and controls. The two SNP profiles -1031CT, -238GG, -857CC, -308GG and -1031TT, -238GG, -857CC, -308AA were found more often in SIDS and may thus be unfavorable. The findings add evidence to the theory that an unfavorable genetic profile in the TNF-alpha gene may be involved in SIDS by exposing the infant to both a high level of and prolonged exposure to TNF-alpha.