Neuromeningeal cryptococcosis is a life-threatening infection of the central nervous system, caused by encapsulated yeast belonging to theCryptococcus neoformansandCryptococcus gattiispecies complexes. Recent data showed that virulence and antifungal resistance are variable for yeasts belonging to theC. gattiispecies complex. There is an increase in resistance to fluconazole for yeasts of theC. gattiispecies complex and the virulence is variable according to the genotype. In the present study, (i) we explored and compared the mechanisms of resistance to fluconazole betweenC. deuterogattiiclinically resistant strains and induced fluconazole-resistant strains by exposure to fluconazole in vitro, and (ii) we studied their virulence in theGalleria mellonellastudy model. We demonstrated that the fluconazole resistance mechanisms involved were different between clinically resistant strains and induced resistant strains. We also demonstrated that fluconazole-induced resistant strains are less virulent when compared to the original susceptible strains. On the contrary, the clinically resistant strain tested maintains its virulence compared to fluconazole-susceptible strains of the same sequence type.