The effectiveness of intermittent preventive treatment during pregnancy with sulfadoxine-pyrimethamine (IPTp-SP) against malaria and anemia is unclear because of the spread of SP-resistant Plasmodium falciparum. This study evaluates the effectiveness of IPTp-SP among pregnant women attending the antenatal clinic at Korle-Bu Teaching Hospital in Accra, Ghana. A cross-sectional study comparing malaria and anemia prevalence among pregnant women using IPTp-SP with non-IPTp-SP users was conducted during June-August 2009. A total of 363 pregnant women (202 of IPTp users and 161 non-IPTp users) were recruited. A total of 15.3% of IPTp users had malaria compared with 44.7% of non-IPTp users (P < 0.001). A total of 58.4% of non-IPTp users were anemic compared with 22.8% of IPTp users (P < 0.001). When we controlled for other variables, the difference in the prevalence of malaria (odds ratio = 0.18, 95% confidence interval = 0.08-0.37) and anemia (odds ratio = 0.20, 95% confidence interval = 0.12-0.34) remained significant. The recommended IPTp-SP regimen is useful in preventing malaria and anemia among pregnant women in Ghana.