We report two patients with hyperimmunoglobulin E syndrome who had fingernail onychomycosis and were successfully treated with fluconazole. Relapse of oral candidiasis, but not of onychomycosis, was observed within three months of stopping fluconazole. There were no adverse effects from this therapy. Based on our experience, we think that fluconazole may be useful in the treatment of onychomycosis in patients with hyper-IgE syndrome as well as in those with other primary immunodeficiency disorders.