The purpose of the study was to evaluate the effectiveness of caspofungin and voriconazole in the treatment of experimental Aspergillus otits media in an experimental rabbit model. A total of 30 New Zealand white rabbits were divided into four treatment groups and one control group. The rabbits were immunosuppressed by cyclophosphamide and triamcinolone acetonide. The right ear of each rabbit was infected by an injection of the inoculum of 0.1 ml (8.6 x 103 CFU/0.1 ml) of Aspergillus fumigatus into the middle ear cavity. At 72 h after the inoculation, amphotericin B 1 mg/kg per day (n = 6), itraconazole 10 mg/kg per day (n = 6), voriconazole 10 mg/kg per day (n = 6) and caspofungin 5 mg/kg per day (n = 6) were injected to each treatment group. No antifungal drug was administered to the control group (n = 6). Clinical and histopathological examination scores and microbiological analysis of middle ear mucosa were compared.There was statistically significant difference in the clinical scores, histopathological scores, and mean CFU/g between the treatment and control groups (P < 0.05). There was no statistically significant difference among the treatment groups in the clinical and histopathological scores, whereas there was statistically significant difference in the mean CFU/g (P < 0.05). The mean CFU/g of amphotericin B and caspofungin groups were similar and both were lower than the itraconazole and voriconazole groups. Also, the mean CFU/g of voriconazole group was lower than the itraconazole group (P < 0.05). Caspofungin and voriconazole were demonstrated at least as effective as amphotericin B and itraconazole. We suggest that caspofungin and voriconazole may be considered for the treatment of fungal infection of the ear.