The present study examined the effect of single, orally administered, doses of caffeine (600 mg) on diaphragmatic muscle contractility in 6 normal subjects and compared the magnitude of the effect with that of theophylline. The force-generating ability of the diaphragm was assessed from measurements of transdiaphragmatic pressure (Pdi) obtained via catheters in the esophagus and stomach, and the level of diaphragmatic excitation was assessed from the diaphragmatic electromyogram recorded with an esophageal electrode. Caffeine increased Pdi at all levels of diaphragmatic electromyographic activity in all 6 subjects. Increases in the ability of the diaphragm to generate pressure were caused by increases in muscle contractility rather than by changes in end-expiratory lung volume or thoracoabdominal configuration. Theophylline administered in a dose equal to that of caffeine increased Pdi in 5 of the 6 subjects. The magnitude of the increase in Pdi was greater with caffeine than with theophylline, however. The greater effect of caffeine than of theophylline on Pdi was not explained by differences in the blood concentrations of the 2 drugs. Neither drug produced consistent changes in blood pressure or heart rate. We conclude that caffeine, which, like theophylline, augments respiratory muscle contractility, may prove useful in the treatment of selected patients with respiratory muscle weakness.