Background: Asthma is one of the most common chronic diseases in the US, and its prevalence continues to increase. Despite the availability of effective asthma controller medications, many patients with asthma are still not meeting therapeutic goals because of poor disease management. The high disease prevalence combined with the high costs associated with the poor management of asthma, make patients with asthma a costly group to treat for managed care organisations (MCOs) and this motivates decision makers in MCOs to consider both the clinical and economic value of asthma therapies. Objective: To compare the cost effectiveness of first-line controller asthma therapies in patients with mild-to-moderate persistent asthma from an MCO payer perspective. Methods: A decision-analysis model was developed to evaluate the cost effectiveness of fluticasone propionate and salmeterol administered in a single inhaler (salmeterol/fluticasone propionate 50/100 mu g), compared with fluticasone propionate inhaled corticosteroids (FPIC), non-fluticasone propionate inhaled corticosteroids (nFPIC) and leukotriene modifiers. The model estimated costs ($US, year 2005 values) and health outcomes over a 1-year period. Costs and outcomes data were obtained from published clinical trials and observational studies, and model assumptions on the relationship between adherence and effectiveness were evaluated by a panel of experts. Effectiveness measures included symptom-free days and rescue medication-free days. The cost effectiveness of first-line asthma therapies was compared using a step-wise approach, with FPIC as the reference case. Both one-way and probabilistic sensitivity analyses were performed to assess the robustness of results over a range of assumptions. Results: The step-wise comparison found that the additional costs for achieving an incremental effectiveness unit (incremental cost-effectiveness ratio) using single-inhaler salmeterol/fluticasone propionate compared with FPIC was $US9.55 per symptom-free day and $US8.93 per rescue medication-free day. Sensitivity analyses indicated that the model was robust to changes in base-case assumptions. A probabilistic sensitivity analysis showed that, corresponding to a benchmark value of $US 14.8 per symptom-free day, the probabilities that single-inhaler salmeterol/fluticasone propionate, n-FPIC and leukotriene modifiers were more cost effective than FPIC were 98%, 30.7% and 2.1%, respectively. Conclusion: Based on our decision analysis, the additional costs for achieving incremental effectiveness with single-inhaler salmeterol/fluticasone propionate treatment compared with FPIC and nFPIC may be lower than the commonly accepted benchmark value for cost effectiveness, based on published estimates of the utility losses associated with asthma symptoms. Single-inhaler salmeterol/fluticasone propionate may also be more cost effective than leukotriene modifiers.