The precise role of erythrophagocytosis in sickle cell disease is not known. Using hematological data from three studies and 791 subjects comprising of eight epidemiological groups, we found a strong statistical support for the hypothesis that erythrophagocytosis is increased in sickle cell trait, that neutrophils and lymphocytes are the most likely cells involved in erythrophagocytosis in these subjects and that increased erythrophagocytosis may for a mechanistic explanation for an increased risk of vaso-occlusive crisis in sickle cell trait. Statistically, erythrophagocytosis was not increased in subjects with homozygous sickle cell disease. Our findings offer an interesting mechanistic implication about the presence of a strong autoimmune component of sickle cell trait that can be explained by the well recognized interplay between the receptor molecule signal regulatory protein-alpha (SIRP-alpha) on the phagocyte and its ligand, CD47, on the red blood cell. Our findings also support further and closer evaluation of the other hypothesized mechanisms by which neutrophils and lymphocytes partake in differential degree of erythrophagocytosis in subjects heterozygous for the sickle hemoglobin. Finally, translation of these findings into a clinical realm suggests that the extent of erythrophagocytosis, as measured by peripheral blood hematological indicators, can serve as an important indicator of the likelihood of future vaso-occlusive crisis events in subjects of sickle cell trait.