Sixteen adult subjects in a clinical steady state had four consecutive histamine inhalation tests on the same day when they were not receiving oral theophylline medication. The provocative concentration of histamine causing a 20% fall in FEV1 (PC20) was used to assess the response. They were then administered active or placebo sustained-release theophylline preparations according to a double-blind, randomized 4.4.1. two-treatment crossover design. Medication was administered for a minimum of 3 consecutive days, and PC20 was reassessed on 4 different days, 3 to 4 hours after receiving active or placebo medication (two visits for each medication). A significant but small bronchodilator and blocking effect on histamine excitability was demonstrated for the active medication. This latter effect was present even by adjusting for changes in baseline airway caliber and for the intraindividual variability of the four PC20 values obtained on day 1. We conclude that theophylline partially blocks bronchial responsiveness to inhaled histamine.