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Background: In previous open-label noncomparative clinical trials, both fluconazole and itraconazole were effective therapy for progressive forms of coccidioidomycosis.Objective: To determine whether fluconazole or itraconazole is superior for treatment of nonmeningeal progressive coccidioidal infections.Design: Randomized, double-blind, placebo-controlled trial.Setting: 7 treatment centers in California, Arizona, and Texas.Patients: 198 patients with chronic pulmonary, soft tissue, or skeletal coccidioidal infections.Intervention: Oral fluconazole, 400 mg/d, or itraconazole, 200 mg twice daily.Measurements: After 4, 8, and 12 months, a predefined scoring system was used to assess severity of infection. Findings were compared with those at baseline.Results: Overall, 50% of patients (47 of 94) and 63% of patients (61 of 97) responded to 8 months of treatment with fluconazole and itraconazole, respectively (difference, 13 percentage points [95% CI, -2 to 28 percentage points]; P = 0.08). Patients with skeletal infections responded twice as frequently to itraconazole as to fluconazole. By 12 months, 57% of patients had responded to fluconazole and 72% had responded to itraconazole (difference, 15 percentage points [CI, 0.003 to 30 percentage points]; P = 0.05). Soft tissue disease was associated with increased likelihood of response, as in previous studies. Azole drug was detected in serum specimens from all but 3 patients; however, drug concentrations were not helpful in predicting outcome. Relapse rates after discontinuation of therapy did not differ significantly between groups (28% after fluconazole treatment and 18% after itraconazole treatment). Both drugs were well tolerated.Conclusions: Neither fluconazole nor itraconazole showed statistically superior efficacy in nonmeningeal coccidioidomycosis, although there is a trend toward slightly greater efficacy with itraconazole at the doses studied. [ABSTRACT FROM AUTHOR]