In this inter-relationship, we hypothesize that activation of sphingomyelinase-ceramide pathway might play a crucial role in the pathogenesis of COVID-19: (1) epithelial tissue damage to infection and subsequent repair might result in the serum appearance of ASM in critically ill patients, of which the activity is associated with severity markers, as well as (2) in rather long-lasting compartments (lipoproteins and erythrocytic membranes) the change of activity is mirrored by an increase of ceramides, reflecting the deteriorated status of the patients. The gene discussed is SMPD1; the disease is COVID-19.