The Federal Drug Administration (FDA) approved the use of Fluticasone 250 microg/Salmeterol 50 microg 1 puff bid for maintenance therapy in patients with COPD associated with chronic bronchitis. Short-acting beta agonists (SABA) have been the recommended rescue medication; however, previous studies have shown that combination short-acting Albuterol (alb) /Ipratropium bromide (IB) has superior bronchodilator properties to albuterol alone in patients with COPD. The safety and efficacy of Albuterol compared to Albuterol/Ipratropium bromide as rescue medications for COPD patients on maintenance combination therapy of ICS/LABA has not been evaluated. Double-blind randomized crossover trial with COPD subjects receiving Fluticasone/ Salmeterol 500 microg/50 microg (Flu/Sal) 1 puff twice daily and 2 puffs of Albuterol Sulfate (90 microg micrograms per inhalation) or 2 puffs of Albuterol (90 microg/puff and Ipratropium Bromide 18 microg/puff. Either Albuterol Sulfate (90 micrograms/puff) or Alb (90 micrograms/puff)/IB used prn for 3 weeks before crossing over to the other rescue formulation. This is a non-inferiority study where safety and efficacy outcomes were serially assessed, including adverse events, Baseline (BDI)/Transition Dyspnea Index (TDI), St. George Respiratory Questionnaire (SGRQ), SF36, diary cards, 24-hour cardiac monitoring, potassium and glucose levels and other adverse events. Twenty subjects completed the study. The mean age was 62.5 (+/- 14.5); 12 were males. The mean baseline FEV(1) (range) was 1.12 L (0.56-1.67) or 40.6 (21-65)% predicted. There were no statistically significant differences between either rescue inhaler formulation with regard to measures neither of lung function or dyspnea nor in terms of safety parameters of cardiac monitoring, glucose and potassium levels and other adverse events. SABA and combination SABA/Ipratropium bromide are equally safe and efficacious as rescue inhalers for patients on combination Fluticasone 500 microg/Salmeterol 50 microg.