Prostaglandin E1 (PGE1) is a bronchodilator in humans, but the effect of this prostaglandin on airway responsiveness in asthmatic subjects is not known. The purpose of this study was to examine the effect of oral PGE, treatment on airway responsiveness to inhaled histamine and methacholine in asthmatic subjects. The subjects had inhalation tests performed on separate study days over a period of 2 weeks. PGE1 (200 μg 4 times daily) or placebo was taken in a double-blind fashion for 4 consecutive days. Each week, after three days of treatment, a histamine or methacholine inhalation test was performed on one day, followed by an inhalation test with the alternative agonist the following day. Baseline forced expired volume in 1 s (FEVI) values were similar before each inhalation test on each study day (P=0.81). However, both histamine and methacholine airway responsiveness decreased following PGE1 treatment. The mean provocative concentration of histamine causing a 20% fall in FEVI (PC20 histamine) on the placebo day was 1.47 mg/ml (%SD 3.05) and was 2.35 mg/ml (%SD 2.72) (p < 0.005) during PGE, treatment period. Similarly the PC20 methacholine was 1.84 mg/ml (%SD 2.30) on the placebo day and was 2.53 mg/ml (%SD 2.06) during PGE, treatment period (p=0.025). This study demonstrates that oral PGEI, administered in doses which did not change airway caliber, can reduce airway responsiveness in mild asthmatics.