The increase in acid sphingomyelinase (aSMase) activity has been implicated in the severity of disease and its fatal outcome. In sepsis, aSMase activity has been shown to continuously increase throughout the continuum from SIRS (systemic inflammatory response syndrome) to severe sepsis. The inhibition of this enzyme with desipramine, a low molecular weight inhibitor, presents promising results in cystic fibrosis patients. We therefore addressed the question of whether secreted aSMase is involved in host response to infection, which is reflected in humoral and functional parameters of immune activation. We identified a dual function of this enzyme in host response where the activity of aSMase is essential during the early phase of host response with respect to bacterial elimination, yet the continuous increase in aSMase activity and ceramide generation presents with detrimental effects in the late phase of host response. We found a different cytokine profile between the genotypes (wt and ko) and yet more striking results following pharmacological inhibition with desipramine (i.e. Inhibition group). We observed a hyperresponsive state in the ko animals highlighted by an overwhelming bacterial burden and inflammatory response with poor outcome (20% survival), similar to wt. We observed a more favorable overall profile in the inhibition group highlighted by abrogated and alleviated cytokine levels and ROS release associated with a repressed gene expression profile. Additionally, desipramine pretreatment resulted in the downregulation in expression of surface markers with subsequent unchanged values in numbers of rolling and sticking leukocytes. We also measured stability in markers of liver dysfunction in desipramine pretreated animals compared to the other two groups. In summation, the altered parameters reflected on survival with a more favorable survival of 42% in the inhibition group. The use of the functional inhibitor desipramine reveals to be promising with respect to treatment of the host response. As it is already FDA approved for the treatment of several human conditions, the present study encourages further research into the use of desipramine for the treatment of host response. The presented data also encourage a clinical study with the use of desipramine in well defined sepsis patients.