To elucidate the impact of nutrition in cystic fibrosis (CF), we compared the phenotypic traits of Cftr -/- mice fed either a lipid-enriched liquid diet (Peptamen) or a standard chow combined with polyethylenglycol osmotic laxative (PEG), two strategies commonly used to prevent intestinal obstruction in CF mice. Survival, growth, liver, and ventilatory status were determined in Cftr -/- and Cftr +/+ mice, followed-up until 120 d. Ventilation was recorded in conscious animals using whole-body plethysmography. We found that the survival rate was similar in Peptamen and PEG Cftr -/- mice. Cftr -/- mice had lower minute ventilation than Cftr +/+ mice, whatever the diet. Both Cftr -/- and Cftr +/+ mice fed Peptamen displayed preadult growth delay compared with PEG-treated animals. Despite subsequent growth catch-up, Cftr -/- mice remained smaller than Cftr +/+ mice, whatever the diet. All Peptamen fed Cftr -/- mice showed hepatomegaly and liver steatosis, which also occurred but to a lesser extent in Peptamen fed Cftr +/+ animals. Therefore, while both treatment strategies are similarly efficient to avoid high mortality at weaning, Peptamen induces preadult growth delay and liver steatosis. These effects of diet are important to consider in future animal studies and also prompt to evaluate high-energy diets in CF patients.