The component drugs of fixed-dose combination bronchodilators may interact in a synergistic manner to antagonize airway contractions. To examine this hypothesis, combinations of ephedrine (E) and theophylline (Th) or salbutamol (S) and theophylline were tested for their ability to relax contracted guinea-pig airway smooth muscle in vitro. The combination bronchodilator effect was compared to the summed effects of the component drugs given individually (i.e. a theoretical additive response, Ta). Relaxation responses to combination bronchodilators were considered less-than-additive if significantly less than Ta, additive if non-significant and greater-than-additive or synergistic if the values were significantly greater than Ta. It was found that the E-Th combinations interacted primarily in an additive fashion to relax contractions induced by histamine, acetylcholine and 5-hydroxytryptamine at concentrations that produced one-half maximal contractile response (ED50). Similarly S-Th combinations interacted in an additive manner to reverse histamine and acetylcholine contractions. In the case of both E-Th and S-Th combinations, the drugs were more effective in reducing the smooth muscle contractions when given during rather than prior to the response. It may be concluded that beta-sympathomimetics and methylxanthines when combined do not interact in a synergistic fashion to produce relaxation of contracted airway smooth muscle.