The dose-related effects of milrinone, a phosphodiesterase (PDE) III inhibitor, on the contractility of fatigued diaphragm were studied in dogs. Animals were divided into three groups of eight each. Diaphragmatic fatigue was induced by intermittent supramaximal bilateral electrophrenic stimulation at a frequency of 20 Hz applied for 30 min. After the production of fatigue, Group I received no study drug; Group II was infused with milrinone (50 mg kg−1 loading dose plus 0.2 mg kg−1 min−1 maintenance dose); Group III was infused with milrinone (50 mg kg−1 loading dose plus 0.5 mg kg−1 min−1 maintenance dose). Diaphragmatic contractility was assessed by measurement of transdiaphragmatic pressure. After the fatigue-producing period, transdiaphragmatic pressure at low-frequency stimulation (20-Hz) decreased from the prefatigued values in all groups (P < 0.05), whereas transdiaphragmatic pressure at high-frequency (100-Hz) stimulation did not change. Compared with Group I, transdiaphragmatic pressure to each stimulus increased during milrinone infusion in Groups II and III (P < 0.05). The increase in transdiaphragmatic pressure was greater in Group III than in Group II (P < 0.05). It is concluded that milrinone is associated with a dose-related effect on the contractility of fatigued diaphragm in dogs.