To compare the efficacy and safety of tiotropium and ipratropium in patients with chronic obstructive pulmonary disease (COPD) in Taiwan. Methods: This double-blind, randomized, placebo-controlled, parallel group study was conducted at six hospitals in Taiwan. COPD patients aged ≥ 40 years, with a forced expiratory volume in 1 second (FEV1) ≤65% of predicted and FEV1/forced vital capacity (FVC) ≤ 70% were enrolled. After a 2-week screening/baseline period, 132 patients were randomized to receive 4 weeks of treatment with either tiotropium 18 μg once daily from a dry powder inhaler (HandiHaler(r)) or two puffs of ipratropium 20 μg four times daily from a metered dose inhaler. The primary outcome was the change in trough FEV1 from baseline to week 4. The secondary outcome measures were trough FVC response, FEV1 and FVC responses at 2 hours postinhalation. Results: After 4 weeks, trough FEV1 had increased by 61.7 + 25.3 mL for tiotropium but decreased by 16.4 + 27.9 mL for ipratropium. The difference between groups was significant (p<0.05; 95% CI, 10-146.1). The trough FVC also increased by 137.2 + 49.3 mL for tiotropium but was decreased by 84.5 + 54.5 mL for ipratropium (p< 0.001; 95% CI, 89.0-354.3). No major drug-related adverse events associated with tiotropium and ipratropium were observed. Conclusion: Tiotropium 18 μg once daily using HandiHaler(r) was significantly more effective than ipratropium 40 p, g four times daily in improving trough FEV1 and FVC over a 4-week period. The safety profiles of both drugs are comparable.