Background: Coccidioidomycosis has reached epidemic proportions in the southwest region of the United States. Despite the greater numbers of cases, isolated anterior segment ocular coccidioidomycosis in the absence of systemic infection continues to be rare, although its incidence may be increasing. Methods: Two patients without clinical evidence of systemic disease and one patient with previously treated pulmonary coccidioidomycosis had granulomatous iridocyclitis and iris nodules that were unresponsive to corticosteroid therapy. All three patients underwent iris biopsy, anterior chamber tap, and washout for histopathologic diagnosis of anterior segment disease, and all subsequently received systemic antifungal therapy. Two patients also received multiple intraocular injections of amphotericin B. Results: Papanicolaou and hematoxylin-eosin-stained preparations of anterior chamber tap and biopsies of the iris in each of these patients showed fibrinopurulent or granulomatous inflammatory exudate with intact and disrupted Coccidioides spherules. Despite aggressive systemic and intraocular therapy, one patient required enucleation for a blind, painful eye. The other two patients continue to have limited visual acuity but with at least partial resolution of the intraocular lesions. Conclusions: Ocular coccidioidomycosis without clinical evidence of systemic involvement is rare. Isolated anterior segment disease is also uncommon; however, because of the current epidemic in the southwest region of the United States, ocular coccidioidomycosis should be considered in any patient who traveled through or lived in endemic areas and who has a granulomatous iridocyclitis associated with iris mass that is unresponsive to corticosteroid therapy.