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Background. In hospital-based studies,α+-thalassemia has been found to protect against severe, life-threatening falciparum malaria. α+-Thalassemia does not seem to prevent infection or high parasite densities but rather limits progression to severe disease—in particular, severe malarial anemia. We assessed to what extent α+-thalassemia influences the association between mild, asymptomatic Plasmodium falciparum infection and hemoglobin concentration. Methods. The study was based on 2 community-based surveys conducted among afebrile children (0.5—8 years old; n =801) in Kenya and Tanzania. Results. Among children without inflammation (whole-blood C-reactive protein concentration ⩽10 mg/L), P. falciparum infection was associated with only small reductions in hemoglobin concentration, and effects were similar across α-globin genotypes. By contrast, the reduction in hemoglobin concentration associated with P. falciparum infection accompanied by inflammation was larger and strongly depended on genotype (normal, —21.8 g/L; heterozygous, —16.7 g/L; and homozygous,—.6 g/L). Relative to children with a normal genotype, this difference in effect was 5.1 g/L (95% confidence interval [CI], —1.0 to 11.1 g/L) for heterozygotes and 17.2 g/L (95% CI, 8.3 to 26.2 g/L) for homozygotes (estimates are adjusted for study site, age, height-for-age z score, and iron deficiency). Conclusions. α+-Thalassemia limits the decline in hemoglobin concentration that is associated with afebrile infections, particularly those that are accompanied by inflammation. [ABSTRACT FROM AUTHOR]