Our study evaluated red blood cell count as supporting hematological index to hematocrit level in predicting severe malarial anemia instead of the hemoglobin levels among malaria-infected children in Ghana. This case-control study was conducted at the Komfo Anokye Teaching Hospital (KATH) in Kumasi, Ghana. The study recruited 139 children, of which 45 were Controls (C), 43 with severe malaria (SM), and 51 with mild malaria (MM). Validated questionnaires were administered to obtain the socio-demographic data from each respondent. Venous blood was obtained for parasitemia count and to determine the hematological profile of each participant. With point of observation, data analysis was done. The mean age of the children was 4.22 ± 2.65 years. Median levels of hemoglobin (Hb) decreased in the order; C > MM > SM (P < 0.0001). There was a reduction in median levels of hematocrit (HCT) (P < 0.0001), RBC (red blood cells count) (<0.0001), from the MM to the SM. Among patients with severe malaria, there were a positive significant spearmen's co-efficient correlations between median levels of RBC (r = 0.652, P = 0.005) and HB (r = 0.640, P = 0.006) individually against HCT. However among the mild malaria patients only RBC (r = 0.884, P < 0.001) was positively correlated against HCT. At a cut-off of <4.0×10
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/uL for RBC and <8.8 g/dL for Hb, RBC (90.4%) recorded a slightly high accuracy in predicting severe falciparum malarial anemia than Hb (86.9%) among the cases. Red blood cell count may be a promising indicator to support hematocrit (<15%) in defining severe malarial anemia than hemoglobin level (<5 g/dL) among malaria-infected children from endemic areas in Ghana.