Background: Malaria is endemic in Nigeria and sickle cell disease is very common in Nigeria and it is believed that malaria is the common cause of morbidity and mortality in children with sickle cell disease (SCD) in our environment as a result malaria prophylaxis is always recommended for them. The study was meant to determine the prevalence, risk factors and effect of malaria in sickle cell disease children. Methods: We recruited 200 febrile children with sickle cell disease and another 200 febrile non sickle cell disease children as control into the study. Two miles of their blood were collected and both thin and thick blood films were made on the same slide, stained by Giemsa methods and examined microscopically. Parasite densities were also determined and packed cell volume (PCV) were enumerated. Results: The study showed that the prevalence of malaria in febrile SCD was 49.0% and 61.0% in non SCD. The PCV of ?20% recorded the highest prevalence of 66.7% while the least prevalent of 41.1% malaria was recorded PCV ?40. In the non SCD the highest prevalent of 63.0% and the least prevalent 56.4%. SCD below 5yrs recorded the highest prevalent of 47.7% malaria while the least 20% malaria ?15yrs. In the non SCD ?5years recorded the highest prevalent while the least was 63.9% malaria. There 108 SCD males examined but 56(51.9%) were positive, while of the 112 non SCD males examined, 69(61.6%) were positive. Of the 98 SCD females examined, 42(42.9%) were positive and 88 non SCD female examined, 53(60.2%) were positive. Of the 73 SCD that uses LLINs, 21(28.8%) were positive while 127 do not used LLINs and had 77(60.0%) malaria, non SCD 51 uses LLINs, 23(45.1%) were positive for malaria, 149 without LLINs had 66.4% malaria. There was no malaria in SCD and non SCD that use insect repellants while 198 SCD that do not use repellants had 98(49.5%) malaria. SCD using door screen had 21.3% and without had 71.2% malaria, while non SCD had 32.6% and those without had 86.7%. SCD on malaria prophylaxis had 33.6% malaria, while without had 60.5% positive. Non SCD using prophylaxis had 23.5% malaria and without 64.5%malaria. SCD that take indigenous herbs at home had 56.9% malaria while without herbs had 40.8%malaria, non SCD that take indigenous herbs at home had 22.8% malaria and without had 93.5% malaria. Conclusion: We conclude that non sickle cell disease febrile children are more susceptible to malaria and have higher parasite densities than sickle cell disease febrile children studied. Therefore we recommend that malaria prophylaxis should not be limited to sickle cell disease children but to all children regardless of their genotype.