Recipients of liver transplantation (LT) are at increased risk for symptomatic coccidioidomycosis, primarily because of chronic immunosuppression and impaired cellular immunity. Unfortunately, no consensus exists regarding optimal posttransplant prophylaxis. In a prior study at our institution, we observed both de novo and recurrent coccidioidomycosis despite targeted antifungal prophylaxis. In response, in February 2011, we instituted a universal prophylaxis program consisting of fluconazole (200 mg daily) for the first posttransplant year. In the current study, we retrospectively reviewed the medical records of all patients who underwent LT between the initiation of universal prophylaxis and July 11, 2013. Patients receiving a second transplant or dual-organ transplant and those who died or did not have follow-up in the 12-month post-LT period were excluded. Data from the universal prophylaxis cohort were compared with previously published data from the targeted prophylaxis era. Of the 160 patients undergoing LT during the study period, 143 met criteria for data analysis. When compared with the 349 patients in the targeted prophylaxis cohort, patients in the universal prophylaxis group were older and had higher rates of pre-LT coccidioidomycosis, asymptomatic coccidioidal seropositivity, posttransplant diabetes mellitus, and renal insufficiency. Fluconazole-related toxicity occurred in 13 of the universal prophylaxis patients, 7 of whom were required to discontinue use of the medication. Coccidioidomycosis developed in 10 of the 391 patients (2.6%) in the targeted prophylaxis cohort and in none of the patients in the universal prophylaxis group (P=0.04). These data strongly support the use of a 1-year antifungal prophylaxis regimen for LT recipients in endemic regions. Liver Transpl 21:353-361, 2015. (c) 2015 AASLD.