Obese patients could be more susceptible to mechanical ventilation (MV)-induced lung injury than non-obese patients due to weight-dependent changes in lung properties. The aim of this study was therefore to evaluate the pulmonary effects of 2 hours low V_T MV in a diet-induced obese mice model, with V_T calculated on either the actual body weight (V_Taw) or the ideal body weight (V_Tiw) . First, we hypothesized that a MV with V_Taw would be associated with altered lung mechanics and an increased lung inflammation. Second, we hypothesised that a MV with a V_Tiw would preserve lung mechanics and limit lung inflammation. We analyzed lung mechanics and inflammation using bronchoalveolar lavage (BAL) cell counts, flow cytometry tissue analysis and histology. Lung mechanics and inflammation were comparable in control and obese mice receiving V_Tiw. By contrast, obese mice receiving V_Taw had significantly more alterations in lung mechanics, BAL cellularity and lung influx of monocytes as compared to control mice. Their monocyte expression of Gr1 and CD62L was also increased. Alveolar neutrophil infiltration was significantly increased in all obese mice as compared to controls. In conclusion, our findings suggest that protective MV with a V_Taw is deleterious, with a marked alteration in lung mechanics and associated lung inflammation as compared to lean mice. With V_Tiw, lung mechanics and inflammation were close to that of control mice, except for an increased alveolar infiltrate of polymorphonuclear neutrophils. This inflammation might be attenuated by a blunted recruitment of inflammatory cells associated with obesity.