OBJECTIVE: To evaluate and compare the cost-effectiveness of long-acting bronchodilators by estimating incremental costs per quality-adjusted life-year (QALY) gained in patients with moderate to severe chronic obstructive pulmonary disease. METHODS: This cost-effective analysis was conducted from a third-party payer's perspective. The study was a retrospective pooled analysis, and the effectiveness evidence was derived from a systematic review of literature published from January 1, 1980, to April 14, 2006. Incremental QALYs were estimated by converting the St George's Respiratory Questionnaire scores Into EuroQoL-SD scores and using these combined scores as the summary benefit measure. RESULTS: The incremental cost per additional QALY was $26,094 (range, $11,780-$77,214) for tiotroplum and $41,000 (range, $23,650-$98,750) for salmeterol compared with placebo. The cost per QALY gained was lower with tiotropium compared with salmeterol or ipratropium based on either the pooled data of available trials or a head-to-head trial. Treatment with tiotroplum could save $391 per year while gaining 13 quality-adjusted days compared with ipratropium. CONCLUSION: Tiotropium appears to be more cost-effective than the alternatives and may be the preferred agent for maintenance therapy in patients with moderate to severe chronic obstructive pulmonary disease. Compared with ipratropium, tiotroplum could be cost saving. Because of the wide ranges of cost-effectiveness ratios for tiotropium and salmeterol and the significant overlap between them, a large prospective head-to-head trial would help address the uncertainty and confirm the results of this analysis.