Abstract. There is accumulating evidence for the involvement of genetic factors in the human response to malaria infection, mostly based on results obtained in studies of severe clinical malaria. The role of major gene(s) controlling blood parasitemia levels in human malaria has also been detected by means of segregation analysis. To confirm and to localize such gene(s), we performed a sib-pair linkage analysis investigating the role of five candidate chromosomal regions: 6p21 (HLA-tumor necrosis factor region), 2q13-q21 (genes coding for interleukin-1 ␣ and ), 14q11 (locus coding for the ␣ chain of T cell antigen receptor), 7q35 (gene cluster for the  subunit of T cell receptor), and 5q31-q33, which includes several candidate genes and was recently linked to a locus controlling infection levels by Schistosoma mansoni, denoted as SM1. The analysis was carried out on nine families from a southern Cameroon village, and the phenotype under study was blood infection levels with Plasmodium falciparum. No linkage was found with any of the four markers outside the 5q31-q33 region. A trend in favor of linkage was observed in the distal part of the 5q31-q33 region, especially with the marker D5S636 (P Ͻ 0.05 using the Monte Carlo P value), which was the marker that provided the highest evidence for linkage with SM1. These results suggest that a locus influencing P. falciparum levels in malaria could be located in the same genetic region as that containing SM1, indicating that the 5q31-q33 region may be critical in the control of different parasite infections.Malaria is a major cause of morbidity and mortality in tropical countries, especially in young children. The profound influence that the genetic makeup of the host has on resistance to malaria has been established in numerous animal studies, 1 and there is also accumulating evidence for the involvement of such genetic factors in the human response to malaria infection. This genetic control can be investigated in humans through different malaria related phenotypes such as clinical phenotypes (e.g., severe malaria), immunologic phenotypes (e.g., levels of immune response induced by malaria antigens), or parasitologic phenotypes (e.g., levels of infection). Numerous population studies have focused on severe malaria and supported the important protective role of several genetic disorders of the red blood cell, such as abnormal hemoglobins 2, 3 or glucose-6-phosphate dehydrogenase deficiency, 4 and of certain HLA antigens. 5 Similarly, homozygotes for a variant of the tumor necrosis factor-␣ (TNF-␣) region were found to have an increased risk of cerebral malaria independently of their HLA alleles, 6 and the functional consequence of this variant upon TNF-␣ gene expression has been recently established.7 More conflicting results exist with respect to the direct implication of HLA genes in the genetic regulation of immune responses induced by malaria vaccine antigens. [8][9][10] Different studies have investigated the role of genetic factors in parasitologic phenotypes. I...