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Rationale: Some patients with severe asthma are immunologically sensitized tooneormorefungi, a clinical entity categorized as severe asthma with fungal sensitization (SAFS). It is not known whether SAFS responds to antifungal therapy. Objectives: To evaluate the response of SAFS to oral itraconazole. Methods: Patients with severe asthma sensitized to at least one of seven fungi by skin prick or specific IgE testingwererecruited. Allhad total IgE less than 1,000 IU/ml and negative Aspergillus precipitins. They were treated with oral itraconazole (200 mg twice daily) or placebo for 32 weeks, with follow-up for 16 weeks. Measurements and Main Results: The primary end point was change in the Asthma Quality of Life Questionnaire (AQLQ) score, with rhinitis score, total IgE, and respiratory function as secondary end points. Fifty-eight patients were enrolled, of whom 41% had been hospitalized in the previous year. BaselinemeanAQLQscorewas4.13 (range, 1-7). At 32 weeks, the improvement (95% confidence interval) in AQLQ score was +0.85 (0.28, 1.41) in the antifungal group, compared with a -0.01 (-0.43, 0.42) change in the placebo group (P = 0.014). Rhinitis score improved (-0.43) in the antifungal, and deteriorated (+0.17) in the placebo group (P = 0.013). Morning peak flow improved (20.8 L/minute, P = 0.028) in the antifungal group. Total serum IgE decreased in the antifungal group(-51 IU/ml) but increased in placebo group (+30 IU/ml) (P = 0.001). No severe adverse events were observed, but seven patients developed adverse events requiring discontinuation, five in the antifungal group. Conclusions: SAFS responds to oral antifungal therapy as judged by large improvements in quality of life in about 60% of patients. Clinical trial registeredwithwww.controlled-trials.com (ISRCTN61552714).