Our objective was to develop new approaches to the chemotherapy of invasive infections caused by Fonsecaea monophora. The in vitro effects of a combination of terbinafine with itraconazole on 18 clinical isolates were evaluated using a checkerboard microdilution method. The mode of interaction between the two drugs on the 18 isolates was analyzed using fractional inhibitory concentration index (FICI) analysis. FICI analysis demonstrated that 12 (67%) were synergistic, 4 (22%) were additive, and 2 (11%) were indifferent, with no antagonism being observed. The minimal inhibitory concentrations (MICs) obtained with the terbinafine-itraconazole combination were within levels that can be achieved in plasma at clinically relevant doses. Our results indicate the terbinafine-itraconazole combination may be an effective therapy for Fonsecaea monophora infection, which should be tested in clinical setting with patients with this disease.