Sphingolipids are a class of lipids containing a backbone of sphingoid bases that can be produced de novo through the reaction of palmitate and serine and further metabolized through the activity of various enzymes to produce intermediates with diverse roles in cellular processes and signal transduction. One of these intermediates, sphingosine 1-phosphate (S1P), is stored at high concentrations (1 μM) in red blood cells (RBCs) and directs a wide array of cellular processes mediated by 5 known G-protein coupled receptors (S1P₁-S1P₅). In this study, we show that RBC membrane alterations in sickle cell disease enhance the activation acid sphingomyelinase by 13%, resulting in increased production and storage of sphingosine (2.6-fold) and S1P (3.5-fold). We also show that acid sphingomyelinase enhances RBC-derived microparticle (MP) generation. These MPs are internalized by myeloid cells and promote proinflammatory cytokine secretion and endothelial cell adhesion, suggesting that potential crosstalk between circulating inflammatory cells and MPs may contribute to the inflammation-rooted pathogenesis of the disease. Treatment with amitriptyline reduces MP generation in vitro and in vivo and might be used to mitigate inflammatory processes in sickle cell disease.