Tumor necrosis factor alpha (TNF alpha) is thought to be a critical mediator of malaria fever, and mild malaria was previously reported to be linked to the MHC region containing the tumor necrosis factor alpha gene (TNF). Thirty-four families from Burkina Faso were analyzed to test for linkage between polymorphisms within the MHC region and mild malaria using the maximum-likelihood-binomial (MLB) program. Two-point analysis indicated linkage of mild malaria to TNFd (LOD = 3.27; P = 5.44 x 10(-5)). Using multipoint analysis, we also found evidence for linkage of mild malaria to the MHC region, with a peak close to TNF (LOD = 3.86; P = 1.22 x 10(-5)). Our results support genes within the MHC region being involved in mild malaria. In particular, the genetic variation within TNF may influence susceptibility to mild malaria. Nevertheless, TNF-238, TNF-244 and TNF-308 polymorphisms are unlikely to explain linkage of mild malaria to the MHC region, and the causal mutations remain to be identified.