Objective: To evaluate all-cause mortality and cost of treatment in patients with refractory invasive aspergillosis (rIA) treated with either posaconazole or other systemic anti-fungal (SAF) therapies. Methods: All-cause mortality and cost of salvage therapy of posaconazole oral suspension (800 mg/day) and other SAF treatments were assessed using a multicenter clinical study in patients with IA refractory to or intolerant of conventional antifungal therapy. Data from external controls were collected retrospectively providing a comparative reference group. All patients had failed to improve or progress with prior SAF therapies. Prior SAF treatments for the majority of patients were liposomal amphotericin B, amphotericin B, or itraconazole. Cases of aspergillosis deemed evaluable by a blinded data review committee included 107 posaconazole and 86 control subjects (modified intent-to-treat population). The populations were comparable regarding pre-specified demographic and clinical characteristics. All-cause mortality were analyzed using the survival technique. Economic evaluations were conducted using survival data and costs of pharmacotherapy one year post therapy (2007 Canadian dollars). Results: Significantly more posaconazole-treated patients responded to therapy as compared with other SAF therapies. Patients with rIA treated with posaconazole appeared to confer a highly significant survival benefit over the control cases. The cumulative rates of survival at 30 days and at the end of therapy were 74% and 38%, respectively. For controls, those survival rates were 49% and 22%, respectively. The Kaplan-Meier survival curves were significantly different (P=0.0003). In addition, posaconazole appeared to be a cost-saving option for the treatment of rIA compared with the active comparator receiving standard SAF treatments ($14,839 vs. $38,158). Sensitivity analyses demonstrated the robustness of the results over a range of alternative values for costs and outcomes. Conclusion: Treatment with posaconazole compared with other SAF treatments provided a significant survival benefit in patients with rIA at lower cost of drug therapy.