BACKGROUND: The use of sulfadoxine-pyrimethamine (SP) for intermittent preventive treatment in pregnancy (IPTp) is threatened by the spread of resistance to SP. Therefore, we studied the efficacy, safety, and tolerance of amodiaquine (AQ) or the combination of AQ and SP (SPAQ) as possible alternative treatments. METHODS: The study was performed in Ghana from June 2004 through February 2007. Women were individually randomized to receive IPTp with SP (n=1328), AQ (n= 986), or SPAQ (n=1328). Incidences of anemia, peripheral anemia, and placental parasitemia at delivery were assessed for paucigravidae, as were the birth weights of their infants. Delivery outcomes and the incidence of adverse events were investigated for all women. RESULTS: The prevalences of anemia (as defined by a hemoglobin concentration of <11.0 g/dL) at delivery were comparable between the SP and AQ groups and between the SP and SPAQ groups. Similarly, there was no significant difference between the SP and AQ groups or between the SP and SPAQ groups with regard to the incidences of low birth weight (LBW). Women who received AQ or SPAQ were more likely to report adverse events than were those who received SP. CONCLUSION: The effects of IPTp with AQ or SPAQ on maternal anemia and LBW were comparable to the effects of IPTp with SP; however, IPTp regimens that contain AQ are unlikely to be useful as an alternative to IPTp with SP in Ghana, because of a high frequency of associated adverse events. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT00146783 .