Background: In 2014, Nigeria scaled up to at least 3 doses of intermittent preventive therapy in pregnancy with Sulphadoxine-Pyrimethamine (ITPp-SP). While the fact of existing evidence as to the superiority of SP3 over SP2 was shown by WHO back in 2012, the Nigerian Government domesticated it in her Federal Ministry of Health guideline for the prevention of Malaria in pregnancy of 2014. Studies leading to the pronouncement were mainly in East African Countries where the density / pattern of infection as well as the species of the plasmodium tend to vary with what is occasionally obtainable in West African sub-region including, Nigeria. There was an apparent need for the measurement of the effectiveness in hyper / holo-endemic country like Nigeria. Aim: To determine the efficacy and safety of 3-doses compared with 2-doses of intermittent preventive therapy in pregnancy with sulphadoxine-pyrimethamine (SP) for the prevention of placental malaria and associated low birth weight. Subjects and Methods: Nine hundred and twenty (920) pregnant women were randomised to receive either 2 doses (SP2) or 3 doses (SP3) of sulphadoxine-pyrimethamine between December 2013 and August, 2014. Pre-delivery blood samples were collected for maternal haemoglobin as well as placenta blood samples for placenta parasitaemia. The Neonates were weighed and followed-up. Prevalence of placental parasitaemia, low birth weight (LBW), preterm birth and anaemia were analysed using intention-to-treat (ITT) and per-protocol (PP) analysis. Results: Data from 910 women were analysed (458 in the SP2 and 452 in the SP3 group). Overall, the incidence of placenta parasitaemia, low birth weight and pre-delivery anaemia in pregnancy were significantly lower among the SP3 group compared with those that had two doses (Sp2), p < 0.001for all factors. There was no neonatal jaundice in either group. Conclusion: Addition of a third dose of SP to the current popular two doses of IPT-SP demonstrated a better outcome in the reduction of placenta parasitaemia, LBW and, anaemia in pregnancy among many more advantages. It would be worthwhile to domesticate the at least, 3 dose of IPTp-SP to all pregnant women in our current practice.