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Background: Malaria is a leading cause of maternal and perinatal morbidity and mortality in sub Saharan Africa. Intermittent Preventive Treatment (IPT) with Sulphadoxine-Pyrimethamine (SP) has been proven efficacious in reducing the burden of malaria in pregnancy. However its use is contraindicated in some individuals and malaria resistance to SP has been reported. Therefore there is a need to seek for effective alternatives. This study sought to compare the effectiveness of proguanil versus SP for malaria chemoprophylaxis in pregnancy. Methodology: This was a randomised controlled trial of women attending antenatal clinic at the University of Port Harcourt Teaching Hospital, Nigeria from January 2010 to September 2010. Three hundred and fifty participants were recruited at booking, randomized into two groups using a table of random numbers and monitored till delivery. One group received daily proguanil while the other received SP for malaria prophylaxis. Blood samples were taken for their haematocrit and malaria parasites at booking and delivery. The results were compared. Data management was with SPSS 15 for Windows® statistical soft ware. A p-value of less than 0.05 was considered statistically significant. Results: The prevalence of maternal malaria parasitaemia in this study was 29.9% at booking and 12.5% at delivery. The prevalence at delivery in women given SP and proguanil was 10.6% and 14.4% respectively. This was not statistically significant (P=0.429). There was no statistical difference in the incidence of preterm delivery (P=0.262), cord blood parasitaemia (P=0.385), low birth weight (P=0.175) and birth asphyxia (P=0.367) between the two study groups. Conclusion: There was no significant difference between intermittent preventive treatment with sulphadoxinepyrimethamine and the use of daily proguanil so larger studies with proguanil are warranted.