Diaphragmatic fatigue may play an important role in precipitating acute respiratory failure. Pharmacologically, theophylline and beta-2 agonists have been used to improve diaphragmatic contractility. We designed experiments to study the effects of albuterol, a beta-2 agonist, on diaphragmatic fatigue in humans. In 5 normal subjects, fatigue was induced by breathing through an inspiratory resistance. Studies were done at 2 levels of diaphragmatic tension-time index (TTdi) of 0.25 and 0.30. At each TTdi, either placebo or albuterol (4 mg three times daily) was taken for 3 days. All subjects experienced side effects of sympathetic stimulation. Albuterol did not significantly increase the strength of the fresh diaphragm. With a TTdi of 0.25, values for mean endurance time were 649 +/- 250 (mean +/- SE) and 552 +/- 161 s, respectively, in placebo and albuterol runs. Respective values for TTdi of 0.30 were 109 +/- 14 and 143 +/- 27 s. During recovery, the mean values for the time needed for maximal transdiaphragmatic pressure (Pdimax) to reach 90% of the prefatigue Pdimax were 891 +/- 370 and 1043 +/- 394 s, respectively, for placebo and albuterol runs (TTdi = 0.25). Respective values for TTdi of 0.30 were 219 +/- 57 and 231 +/- 108 s. We conclude that, in humans, albuterol has no significant effect on the strength of the fresh or fatigued diaphragm, diaphragm endurance time, or the recovery of Pdimax from fatigue.