Objective: Invasive fungal infections (IFIs) have emerged as the major infection-related cause of morbidity and mortality in patients undergoing transplantations. A recent RCT in allogeneic hematopoietic stem cell transplantation (HSCT) recipients with grade 2-4 or extensive chronic graft-versus-host disease compared the efficacy of posaconazole and fluconazole in the prevention of IFIs. At the end of the fixed 112-day treatment period, posaconazole was as effective as fluconazole in preventing IFIs (5% vs. 9%); significantly reduced breakthrough Aspergillus infections (2% vs. 7%, p=0.0059); and decreased IFI-related mortality (1% vs. 4%; p=0.0413). We evaluated posaconazole cost-effectiveness from the Canadian health care system perspective. Methods: A trial-based decision-analytic model was developed. The probabilities of experiencing an IFI, IFI-related death, and death from other causes over 112 days post treatment were estimated. To extrapolate results beyond the trial, the model was extended to a lifetime horizon using 1-month Markov cycles in which mortality rate was specific to the underlying disease obtained from clinical data. Pharmacotherapy and IFI-related costs were estimated using published literature. The model was used to estimate costs, life-years saved (LYS), and the incremental cost-effectiveness ratio (ICER) of posaconazole vs. fluconazole (2007 CND$). Results: Posaconazole appeared to be more effective with increased LYS (7.95 vs. 7.81) however, more costly ($16,784 vs. $11,760) than the alternative over a lifetime horizon. The ICER of posaconazole was $34,668/LYS compared to fluconazole. A second-order probabilistic Monte Carlo sensitivity analysis was conducted to assess the effects of parameter uncertainty, particularly concerning treatment efficacy and costs of IFIs. There was a 4% probability that posaconazole was both more effective and less costly than Fluconazole, and a 66% probability that posaconazole ICER was at or below the $50,000/LYS threshold. Conclusion: In addition to the proven efficacy, posaconazole appeared to be cost-effective relative to fluconazole in the prophylaxis of IFIs among patients undergoing allogeneic HSCT.