Ten patients with moderate to severe asthma (mean FEV1+/-SD: 57.3+/-5.8% of predicted) participated in this 4-day single-blind, placebo-controlled, crossover study, aimed to comparatively evaluate the bronchodilating effects of a single dose of inhaled salmeterol (50 microg) and oral slow-release theophylline (Theo-Dur, 600 mg tablets), used either alone or in combination. In particular, FEV1 was recorded at baseline and 2, 4, 6, 8, 10, and 12 h after drug administration; at the same times, with the exception of the 12 th h, theophylline plasma concentrations were also measured. When compared to theophylline, bronchodilation induced by salmeterol was characterized by an earlier onset, a greater magnitude, and a longer duration. Given in combination with salmeterol, theophylline elicited a further slight increase in airway calibre with respect to the bronchodilator action of the beta2-agonist alone, with FEV1 changes which resulted to be statistically significant at the 4th, 6th and 8th h after administration (p<0.05, p<0.03 and p<0.05, respectively). At the 4th h theophylline reached serum levels included within the therapeutic range, which were persistently maintained at least until the the 10th h. Therefore, our findings suggest that inhaled salmeterol and oral slow-release theophylline, the latter acting within the range of therapeutic plasma concentrations, exert additive bronchodilating effects in asthmatic patients with moderate to severe airflow limitation.