Toll-like receptors (TLRs) are involved in recognition of and response to Plasmodium falciparum. In 304 primiparous Ghanaian women, we examined whether common TLR4 and TLR9 polymorphisms influence susceptibility to and manifestation of malaria during pregnancy. The TLR variants did not affect P. falciparum prevalence or parasite density. However, in P. falciparum-infected women, both the TLR4 Asp299Gly and the TLR9 T-1486C polymorphisms increased the risk of low birth weight in term infants 6-fold, and, additionally, TLR4 Asp299Gly increased the risk of maternal anemia 5-fold; preterm delivery was not associated with these TLR variants. These findings suggest that TLR4 and TLR9 play a role in the manifestation of malaria during pregnancy.