We compared genome-wide transcription profiles of whole blood obtained from Ugandan children with acute CM (n=17) or SMA (n=17) and community children without Plasmodium falciparum infection (n=12) and determined the relationships between gene expression, hematological indices, and relevant plasma biomarkers. Results demonstrated both CM and SMA predominantly upregulated enrichment of dendritic cell (DC), inflammatory/TLR/chemokines, monocyte, and antigen presentation modules but downregulated enrichment of lymphocyte modules. Neurodegenerative disease pathways showed modest upregulation during CM. Nrf2-regulated genes were over-expressed in children with SMA compared to CM, especially those with HbSS, corresponding with increased plasma heme oxygenase-1. Reticulocyte-specific gene expression was markedly decreased in CM relative to SMA despite higher hemoglobin levels and appropriate increases in erythropoietin. Viral sensing/IRF2 module expression and plasma IP-10/CXCL10 negatively correlated with reticulocyte-specific signatures. This study concludes that, compared to SMA, CM is associated with downregulation of Nrf2-related and reticulocyte-specific signatures by whole-blood transcriptomics. Future studies are needed to confirm these findings and assess pathways that may be amenable to interventions to ameliorate CM and SMA. Overall design: Total RNA was purified from whole blood and depleted of globin mRNA prior to amplification and processing for gene expression profiling using Illumina HumanHT-12 v4 Expression BeadChip. Samples were processed in three Batches using random sampling and differential expression was performed between the groups (CM, SMA, CC) adjusting for Sickle cell disease status, HRP2 levels, and Batch effects for the following comparisons: CM vs CC; SMA vs CC; CM vs SMA relative to CC.