It has been documented that tiotropium is less likely to induce oxygen desaturation in stable COPD patients compared to long-acting β₂-agonists (LABAs) and combined administration of a LABA and an inhaled corticosteroid (ICS) reduces the potential for acute effects of LABA on blood-gas tensions. In this study, we have compared the acute effects of tiotropium 18μg and salmeterol/fluticasone combination (SFC) 50/250μg on arterial blood gases in 20 patients with stable COPD. Each subject was studied on 2 days, separated from one another by at least 4 days. Blood specimens were taken just before the inhalation and at 15, 30, 60, 180 and 360min after inhalation of each treatment, and spirometry was performed at the same time points. As expected, both treatments significantly improved FEV₁ (greatest changes were 0.20L, 95% CI: 0.13–0.27 at 360min after tiotropium; and 0.13L, 95% CI: 0.06–0.19 at 180min after SFC). The greatest mean changes from baseline in PaO₂ were −1.7 (95% CI: −4.0 to 0.6)mmHg, p=0.134, after tiotropium; −0.8 (95% CI: −2.2 to 0.6)mmHg, after SFC. Both changes were observed after 15min. Both drugs caused a small decrease in PaCO₂ (greater changes: −1.9 (95% CI −3.2 to −0.6)mmHg, p=0.005 at 60min after tiotropium; and −2.4 (95% CI: −3.5 to −1.3) mmHg, p=0.0002 at 180min after SFC). These results indicate that both tiotropium and SFC are able to induce a significant long-last bronchodilation without affecting arterial blood gases. Moreover, they confirm that the impact of tiotropium on PaO₂ is small and without clinical significance and the addition of a LABA to an ICS can reduce the potentially dangerous acute effect of the LABA on blood gases.