Polymorphic variation in two cytokine genes, tumor necrosis factor (TNF) -alpha and -beta, was examined in three ethnic groups, the Bugis, the Makassans, and the Torajans, who inhabit Sulawesi, a large island in the Indonesian archipelago, and formerly a Dutch colony. TNF-alpha and -beta are key molecules in immune responses to infection, and both have been implicated in the pathogenesis and clinical manifestations of parasitic diseases. Several polymorphic variants with the potential to affect cytokine levels in autoimmune diseases and parasitic and bacterial infection have been reported. Two loci in the promoter region of TNF-alpha and two sites in the first intron of TNF-beta were scored in a maximum of 150 Bugis, 168 Makassans, and 58 Torajans. Genotypes at the two TNF-alpha loci are not in Hardy-Weinberg equilibrium because of a deficit of heterozygotes (p < 0.05). However, genotypes at the TNF-beta loci exhibit Hardy-Weinberg equilibrium. A comparison of allelic and genotypic frequencies at all TNF loci across the ethnic groups reveals that the differences are significant for TNFalpha(308) (p < 0.01) and for TNFbeta(NcoI) (p < 0.05). Overall, the distribution of the alleles differs from that seen in the few Asian populations for which data are available (p < 0.05). Construction of 4-locus haplotypes showed that, in addition to the five previously reported, four novel haplotypes were present in Sulawesi. These novel haplotypes were in low frequency, and two were seen only in Bugis (haplotypes F and J) and one (haplotype K) only in Makassans. The other, haplotype D, was present in Makassans and Torajans. Preliminary sampling of other ethnic groups suggests that three of these haplotypes (D, F, and J) may be restricted to Asian or Asian-derived populations. The frequency of the common TNF haplotypes differed between Dutch and Sulawesi populations, and these data also indicated that haplotype E, which has a relatively high frequency in the Dutch (25%), may be a useful marker of Dutch/European admixture in Indonesian populations, in which it is either rare (1%) or absent. The results suggest that unique allelic combinations with potential to influence cytokine secretion are present in Sulawesi, possibly as a consequence of parasite-driven selection, and argue for more extensive investigation of haplotype distribution in parasite-endemic areas.