We previously showed that an acute high dose of corticosteroids (80 mg/kg) with controlled mechanical ventilation (CMV) prevented ventilator‐induced diaphragm dysfunction in rats. We examined whether administration of lower doses of methylprednisolone (5 and 30 mg/kg) would result into a similar protective effect. Rats were assigned to a control group (C) or to 24 h of CMV receiving an im injection of saline (CMV) or 5 (MP‐5) or 30 mg/kg (MP‐30) of methylprednisolone. Diaphragm force was decreased after CMV but was more depressed in MP‐5 while in MP‐30 it was similar to C. Atrophy was more severe in MP‐5 than after CMV while no atrophy was observed in MP‐30. Diaphragm calpain activity was increased after CMV and even more so in MP‐5, while it was similar to C in MP‐30. Caspase‐3 activity was increased after CMV and after MP‐5 and MP‐30. Expression of calpastatin, an endogenous inhibitor of calpain, was decreased in CMV and MP‐5 and similar to C in MP‐30. These data clearly show that the effects of corticosteroids during CMV are dose dependent and are related to calpain activity. The latter was upregulated at low doses and inhibited at high doses. These effects are probably mediated by calpastatin. Supported by Fonds voor Wetenschappelijk Onderzoek‐Vlaanderen and by AstraZeneca Pharmaceuticals