The influence of alpha(+)-thalassemia on malaria in pregnancy was assessed in a cross-sectional study of 530 women in Ghana. Plasmodial infections, alpha(+)-thalassemia, serum levels of C-reactive protein, and antimalarial drugs in urine were determined. The alpha-globin genotypes did not correlate with the prevalence of Plasmodium falciparum-infection and parasite densities. However, Plasmodium malariae tended to be more frequent in alpha(+)-thalassemic women (P = 0.05). Excluding women with residual antimalarials, a significant excess of P. malariae was observed in alpha(+)-thalassemic individuals. Febrile responses (P = 0.05) and inflammation (CRP > 0.6 mg/dl, P = 0.06) appeared to be less common in infected alpha(+)-thalassemic women and were also comparatively rare in parasitemic individuals who harbored double species infections with P. falciparum and P. malariae. Plasmodium malariae may influence the pathogenesis of falciparum malaria leading to a low prevalence of inflammation and febrile responses in alpha(+)-thalassemic women.