OBJECTIVES: To assess the association between drug tolerability and economic impact for prophylaxis of invasive fungal infection (IFI) after allogeneic hematopoietic stem cell transplant (HSCT). METHODS: A prospective open-label multicenter study (IMPROVIT) for primary IFI prophylaxis after HSCT included patients>=12 years who were randomized to receive oral voriconazole(VOR) or oral itraconazole(ITR) from HSCT day for at least 100 and up to 180 days. Data for the first 100 days were analyzed. Medical resource use (MRU) endpoints were valued with 2010 UK costs. Univariate, multivariate, and subgroup analyses were conducted. RESULTS: 224 patients were in the VOR and 241 in the ITR group, with similar demographic distributions (average age 43-year, 59% male, 92% Caucasian). All-cause and study drug intolerance discontinuations were less frequent with VOR than ITR (73% vs 82%, p=0.02; 7% vs 22%, p<0.0001). VOR patients had longer study drug exposure (median: 96 vs 68 days, p<0.0001; mean: 68 vs 60 days, p=0.0162).  Multiple regression showed that ITR patients were 2 times more likely (P=0.0032) to use concomitant antifungals (AF) versus VOR patients. Controlling for treatment and key baseline variables, prophylaxis duration was associated with all key MRU: longer IFI prophylaxis was associated with fewer hospital days (p<0.0001), special unit days (p=0.0001), and less concomitant AF use (p<0.0001). Consequently, treatment exposure was negatively associated with total cost (p<0.0001) and concomitant AF cost (p=0.0035). Patients who had study discontinuation or concomitant AF use incurred 74% (£ 26,972 vs £ 15,484, p<0.0001) and 56% (£ 41,775 vs. £ 26,782, p<0.0001) higher total cost, compared to their counterparts respectively. Eight more prophylaxis days were associated with approximately 1 less hospital day and 5% total cost reduction.  Subgroup analyses showed similar results. CONCLUSIONS: The ability of patients to tolerate and continue their AF prophylaxis after HSCT appears to be associated with significant economic consequences.