To assess the frequency of asymptomatic plasmodial infections in young children living in an area of hyperendemicity, a cohort of 200 children in Gabon was investigated longitudinally. Of 660 cases of Plasmodium falciparum infection, 77% were symptomatic at the time they were identified and only 7% were preceded by an asymptomatic phase of >4 days. Sickle cell trait, glucose-6-phosphate dehydrogenase deficiency, and mutation in the promoter region of tumor necrosis factor (TNF(-376A/-238A)) were significantly associated with asymptomatic P. falciparum infection (P=.03, P=.009, and P<.001, respectively). We conclude that true asymptomatic cases of P. falciparum infection are uncommon in young children and that single measurements or measurements made at long time intervals will lead to a strong underestimation of the incidence of malaria.