Study Objective. To compare the impact of fluticasone propionate versus three leukotriene modifiers-montelukast, zafirlukast, and zileuton-on the cost of asthma within a managed care organization. Design. Retrospective quasi-experimental comparison. Setting. Managed care organization with approximately 350,000 enrollees. Patients. Three hundred forty-seven patients with asthma who received at least two prescriptions for either fluticasone or a leukotriene modifier. Patients receiving both fluticasone and a leukotriene modifier were excluded. Measurements and Main Results. Multivariate analysis was used to compare total asthma-related costs between treatment groups. A significant difference in total asthma-related costs was found between patients receiving fluticasone (adjusted mean cost $511) compared with those receiving a leukotriene modifier ($1092; p=0.0001). Other significant predictors of postindex asthma-related costs were pre-index asthma-related costs, a severity adjustment score, and the diagnosis of chronic obstructive pulmonary disease. Patients taking a leukotriene modifier obtained more short-acting beta-agonists than patients receiving fluticasone (6.49 +/- 4.05 vs 4.30 +/- 3.41, p<0.0001). A survival analysis of time to receive any additional controller therapy revealed that patients receiving fluticasone were significantly less likely to receive another controller than were those receiving a leukotriene modifier (p=0.0014). Conclusion. These results suggest that fluticasone is associated with lower asthma-related costs than leukotriene modifiers.