In this multicenter, observational, retrospective study, the ongoing use of functional inhibitors of acid sphingomyelinase (FIASMA) medications at hospital admission was significantly and substantially associated with reduced 28-day mortality, independent of sociodemographic characteristics, psychiatric or other medical comorbidities, the severity of the infection, or other medications among adult inpatients with COVID-19. Here, SMPD1 is linked to COVID-19.