The aim of this study was to investigate the effects of selective phosphodiesterase inhibitors and their combination with salbutamol on antigen-induced microvascular leakage in the trachea. In actively sensitized anaesthetized guinea-pigs, the non-selective phosphodiesterase inhibitor theophylline (100 mg/kg p.o.) and the selective phosphodiesterase type 4 inhibitor Ro 20-1724 (30 mg/kg p.o.) inhibited antigen-induced microvascular leakage (−73.8% and −44.1%, respectively) as demonstrated by a reduced extravasation of plasma proteins measured by the use of Evans blue dye. No significant reduction in microvascular leakage was seen with (a) the selective phosphodiesterase type 4 inhibitor rolipram (10 mg/kg p.o.), (b) the selective phosphodiesterase type 3 inhibitors milrinone (30 mg/kg p.o.) and SK and F 94-836 (30 mg/kg p.o.) or (c) the selective phosphodiesterase type 1/5 inhibitor zaprinast (30 mg/kg p.o.). Neither Ro 20-1724 nor rolipram and theophylline inhibited microvascular leakage induced by either substance P or histamine. Pretreatment with aerosolized salbutamol (10 μg/ml) potentiated the inhibitory effects of theophylline (−49.8% at 30 mg/kg p.o.) and Ro 20-1724 (−52.6% at 10 mg/kg p.o.) versus antigen-induced microvascular leakage. Furthermore, a significant inhibitory effect of rolipram (10 mg/kg, p.o.) was obtained following pretreatment with this concentration of aerosolized salbutamol. Even at higher concentrations (0.3–2 mg/ml) salbutamol did not augment the corresponding inhibitory effects of rolipram and Ro 20-1724 versus microvascular leakage induced by either histamine or substance P. Theophylline had no effect versus substance P-induced microvascular leakage, but did inhibit it significantly (P<0.05) after pretreatment with aerosolized salbutamol (0.3 mg/ml). The potentiation by salbutamol of the inhibitory effects of both non-selective and selective phosphodiesterase type 4 inhibitors versus antigen-induced microvascular leakage probably results from a synergistic reduction in the release of anaphylactic mediators.