The genetic control of blood infection levels in human malaria remains unclear. Case control studies have not demonstrated a strong association between candidate genes and blood parasite densities as opposed to surveys that have focused on severe malaria. As an alternative approach, we used segregation analyses to determine the genetic control of blood parasitemia. We surveyed 509 residents (53 pedigrees) in a rural area and 389 residents (41 pedigrees) in an urban area during 18 months. Each family was visited 20 times and 28 times in the urban area and in the rural area; the mean number of parasitemia measurements per subject was 12.1 in the town and 14.9 in the village. The intensity of transmission of Plasmodium falciparum was 8-fold higher in the rural area than in the urban area. Using the class D regressive model for both populations, we found that blood parasite densities were correlated between sibs. We obtained strong evidence for a major effect, but we found that the transmission of this major effect was not compatible with a simple Mendelian model, suggesting a more complex mode of inheritance. Moreover, there was a strong interaction between major effect and age, suggesting that the influence of the putative major gene may be more prominent in children than in adults. Further nonparametric linkage studies, such as sib pair analysis, that focus on children would help us better understand the genetic control of blood infection levels.