BACKGROUND: The 2 most common hemoglobinopathies, sickle cell trait and alpha (+)-thalassemia, confer partial resistance to fatal forms of malaria, but the molecular basis for this protection is still not understood. Examination of the relationship between these traits and malaria transmission intensity may provide insights into the protection afforded. METHODS: The distribution of the 2 traits was assessed among children resident in 13 villages in the Eastern Arc Mountains in Tanzania, where Plasmodium falciparum transmission intensity is closely correlated with altitude. Associations between the prevalence of the 2 traits and malariometric indices were investigated by logistic regression. Short tandem repeat (STR) microsatellite allele frequencies were used to assess population substructuring. RESULTS: The frequency of alpha (+)-thalassemia ranged from 10%-25% in high-altitude villages (>1200 m) to 45%-55% in low-altitude villages (<600 m). The carriage rate of alpha (+)-thalassemia decreased by approximately 12% per 100-m increase in altitude (P<.001) and was approximately 50% lower among those with patent parasitemia than among uninfected individuals (P=.014). The prevalence of the sickle cell trait was lower than that of alpha (+)-thalassemia (range, 0%-14%) and was significantly associated with village altitude only (P=.011). STR allele frequencies were similar in all villages. CONCLUSIONS: In this malaria-endemic region of Tanzania, alpha (+)-thalassemia is common and clearly associated with P. falciparum transmission intensity. There was no evidence of population substructuring, and the results are suggestive of selection of the alpha (3.7) allele by malaria.