Despite consistent evidence of a protective effect of α(+)-thalassemia against severe Plasmodium falciparum disease, the mechanisms underlying this protection remain unknown. An increase in risk of Plasmodium vivax malaria in early childhood resulting in a cross-species protection against severe P. falciparum malaria has been proposed as a possible mechanism in Melanesian children. The association of α(+)-thalassemia genotypes with a risk of P. falciparum and P. vivax infection and uncomplicated illness was reassessed in a cohort of 1,112 Papua New Guinean children, followed from 3 to 21 months of age. Three hundred and eighty-nine (35.0%) children were homozygous for α(+)-thalassemia (-α/-α), 506 (45.5%) heterozygous (αα/-α) and 217 (19.5%) homozygous for the wild-type allele. No significant differences in the incidence of P. falciparum (Pf) or P. vivax (Pv) malaria were observed between α(+)-thalassemia homozygote (Pf: incidence rate ratio (IRR)=1.13, CI(95) (0.82, 1.56), P=0.45, Pv: IRR=1.15, CI(95) (0.88, 1.50), P=0.31), heterozygote (Pf: IRR=0.98, CI(95) (0.71, 1.34), P=0.93, Pv: IRR=1.14, CI(95) (0.88, 1.48), P=0.33) and wild-type children. The prevalence of infection with either species did not differ between α(+)-thalassemia genotypes, although densities of P. vivax (but not of P. falciparum) infections were significantly higher in α(+)-thalassemia homozygote and heterozygote children. An excessive risk of moderate-to-severe anemia (Hb<8 g/dl) was observed in α(+)-thalassemia homozygote children (IRR=1.54, CI(95) (1.12, 2.11), P=0.008). This study therefore failed to confirm an increased risk of P. vivax or P. falciparum malaria in very young, α(+)-thalassemic children without significant levels of acquired immunity. This confirms the lack of protection by α(+)-thalassemia against uncomplicated P. falciparum and challenges the hypothesis of immunological cross-protection between P. falciparum and P. vivax as a mechanism underlying α(+)-thalassemia protection against severe P. falciparum disease in Melanesian children.