Background: Cigarette smoking is the primary cause of Chronic Obstructive Pulmonary Disease (COPD). Sphingolipids have been shown to play important roles in the pathobiology of lung diseases with the effects of ceramide on emphysematous changes amongst the best documented. In addition, sphingosine-1-phosphate (S1P) and S1P receptors have also been characterized as mediators in the pathobiology of fibrosis and acute lung injury. Aim: Using state-of-the-art lipidomics supplemented with physiological and molecular endpoints, we assessed the biological responses in the lungs of C57BL/6 mice switching to a prototype modified risk tobacco product (pMRTP) compared to smoking cessation after an initial exposure to 3R4F reference cigarette smoke (CS). Methods: Detailed lipidomics profiles were obtained from the lungs of C57BL/6 mice, a rodent model susceptible to emphysema. Mice were exposed to mainstream CS, pMRTP, or to fresh air (Sham) for up to seven months, or to pMRTP (Switch) or fresh air (Cessation) for up to five months after an initial CS exposure period of two months. Molecular and histopathological parameters were also investigated to characterize the lung inflammatory response and emphysema at different time points. Results: The findings of the present study link CS-induced pathophysiological changes to alterations in lung lipid metabolism, with major impact on both eicosanoids and on the sphingolipidome. Long chain ceramides, gangliosides, and sphingosine were all affected by CS, with increasing effect over time. Levels of these lipids in mice switching to a pMRTP or to fresh air (Cessation) rapidly returned to those of fresh air-exposed mice. Conclusion: A switch to the pMRTP aerosol after 2 months of cigarette smoke exposure tracked closely with the cessation exposure group in all assessed parameters.