Abstract: Homozygous sickle cell disease (genotype HbSS) confers a certain degree of protection to human (especially Africans) Plasmodium falciparum malaria, yet the precise mechanism remains unknown. Recent observations suggest that the mechanism might also involve immune and non-immune components. In this study, the plasma levels of trace elements (Mg, Fe, Zn, Mn, Cu, Cr, Cd and Se) and antioxidants (urea, albumin and total antioxidants) were determined in Nigerians with sickle cell disease with (HbSS+M), or without (HbSS-M) Plasmodium parasitaemia, haemoglobin AA with Plasmodium parasitaemia (HbAA+M) compared with those having haemoglobin AA without Plasmodium parasitaemia (HbAA-M) using spectrophotometric method. The mean level of urea was significantly higher while the total antioxidants (TAS), Mg, Fe, Zn, Mn, Cu, Cr, Cd, Se and albumin were not significantly different in HbAA+M subjects when compared with HbAA-M subjects. In HbSS-M subjects, the levels of Fe, Zn, Mn and TAS were significantly lower while the level of urea was significantly higher when compared with HbSS+M subjects. There were no significant differences in the values of Mg, Cu, Cd, Se and albumin in HbSS-M subjects when compared with HbAA-M. In HbSS+M subjects, significantly lower levels of Fe, Zn, Mn, Cu, Cr, Cd, Se, total antioxidants, but significantly higher level of urea were observed when compared with the HbAA-M subjects. The result of this study revealed an aggravating effect of Plasmodium parasitaemia on deranged levels of trace elements in Nigerians with sickle cell disease.