Aim: The aim of this study was to investigate the in vitro and in vivo activities of pure curcumin, as well as its combination with fluconazole, against Cryptococcus gattii. Methods and Results: The minimal inhibitory concentrations (MIC) of curcumin and its interactions with fluconazole against C. gattii were assessed in vitro using standard methods. This same combination was used to treat C. gattii-induced cryptococcosis in mice. The behavioural and functional assessment of the mice during treatment was also performed. The average MIC for curcumin was 19.8 mu g ml(-1). Its combination with fluconazole resulted in FICS (fractional inhibitory concentration index) values between 0.79 and 2.29. Curcumin (alone or combined with fluconazole) significantly reduced pulmonary damage and fungal burden in the brain. No colonies were found in the brain following combination treatment, which was also confirmed by the improved behaviour of mice. Conclusions: The combination therapy with curcumin and fluconazole was the most effective among the treatments tested, as in addition to reducing the fungal burden and damage on lung tissues, it was able to eliminate the fungal burden in the brain, enhancing the survival of mice. Significance and Impact of the Study: This study points to the possibility of using curcumin in combination with fluconazole as a clinical treatment of cryptococcosis.