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To evaluate the effect of theophylline in patients with ventilator-induced diaphragmatic dysfunction (VIDD).Patients who required mechanical ventilation at least 72 hours, met the criteria for a spontaneous breathing trial, and had evidence of VIDD by ultrasonography were included in the study.Of the 40 patients, 21 received theophylline and 19 did not. Clinical characteristics were similar in the 2 groups. Assessment of VIDD showed no between-group differences in baseline diaphragmatic excursion (DE) of both hemidiaphragms. Changes in DE from baseline to 72 hours (ΔDE) were significantly higher in the theophylline group than in the nontheophylline group in the right (3.5 ± 4.5 mm vs 0.4 ± 2.1 mm; P = .004) and left (3.2 ± 5.1 mm vs 0.1 ± 4.0 mm; P = .03) hemidiaphragms and in the total DE of both diaphragms (6.9 ± 9.1 mm vs 0.5 ± 5.7 mm; P = .02). In the theophylline group, theophylline was effective for the diaphragms with VIDD, whereas it was not effective for the diaphragms without VIDD. ΔDE in the right (rs = − 0.49, P = .006) hemidiaphragm and total Δ DE in both diaphragms (rs = − 0.46, P = .01) correlated negatively with weaning time.Theophylline significantly improved diaphragmatic movements in patients with VIDD. Our results warrant a larger study to determine whether theophylline use has benefits during weaning from mechanical ventilation.