Although antifungal drug resistance in the human fungal pathogen Cryptococcus neoformans is relatively uncommon, fluconazole-resistant strains are problematic for preemptive treatment of cryptococcal antigenemia or during cryptococcal meningitis consolidation therapy. We analyzed activity of the experimental antifungal VT-1129 on 51 clinical Cryptococcus neoformans isolates previously screened for fluconazole resistance; with an emphasis on fluconazole dose-dependent (MIC 16-32 μg/ml) or resistant (MIC ≥ 64 μg/ml) isolates. Overall, the VT-1129 geometric mean MIC was 0.027 μg/ml. The VT-1129 MIC50 was 0.05 μg/ml and 0.25 μg/ml for dose-dependent (n = 27) and resistant isolates (n = 6), respectively. These data suggest VT-1129 shows potential for use against fluconazole-resistant Cryptococcus.