- Introduction: The iron chelator, deferasirox (DFX), has shown to have fungicidal activity against Rhizopus. This work is to investigate the potential antifungal activity of iron chelators, deferoxamine (DFO) and DFX, against cryptococcal isolates and their impacts on expression of cryptococcal ironrelated genes. Methods: Cryptococcus neoformans and Cryptococcus gattii were used to determine the minimal inhibitory concentration (MIC) of DFO and DFX and the fractional inhibitory concentration (FIC) of the combinations between the iron chelators and amphotericin B (AMB). Growth curves of cryptococcal strains in exposure to iron chelators, with and without AMB, were performed. Expression of cryptococcal CFT1, CFT2, and CIR1 genes was determined using semi-quantitative real-time PCR. Results: Both DFO and DFX alone show no antifungal activity against Cryptococcus strains. However, when combined with AMB, the MIC of both DFO and DFX decreased from >200 μg/ml to 6.25 μg/ml for serotypes A and AD. For serotypes B, C and D, the MIC of DFO and DFX decreased from > 200 μg/ml to 6.25 and 12.5 μg/ml, respectively. Likewise, the MIC of AMB decreased for one dilution in all strains when combined with iron chelators, giving the FIC of 0.5 and 1 for DFO+AMB and DFX+AMB, respectively. Growth curve of C. neoformans (serotype A and D) showed a significant growth retardation of the yeast cells when incubated with a combination of sub-MIC concentration of AMB and DFO, compared with either AMB or DFO alone. However, C. gattii (serotype B and C) exhibited significantly less extent in growth retardation in media with DFO+AMB. In contrast, cryptococcal growth retardation was not observed, or minimal, when DFX is used in combination with AMB in all serotypes. When C. neoformans was grown in DFO, the CFT1, CFT2 and CIR1 were expressed for 1.7, 2.0 and 0.9 times of control, respectively. With DFX, the CFT1, CFT2 and CIR1 were expressed for 0.5, 0.6 and 0.3 times of control, respectively. Conclusions: The extent of synergistic effect between DFO+AMB was more than that of DFX+AMB and this is different to Zygomycetes in which DFO enhances fungal growth. CFT1 and CFT2 overexpression seems to be the major mechanism related to growth inhibitory effect of DFO.