MGCD290, a Hos2 fungal histone deacetylase inhibitor, showed modest activity when tested alone (MIC range, 0.12-4 μg/mL; MIC50/90, 0.5/4 μg/mL) against Candida glabrata (n=15; 14 fks mutants; 5 also fluconazole resistant), Candida albicans (8 fks mutants; 2 also fluconazole resistant), Candida tropicalis (4 fks mutants), and Candida krusei (3 fks mutants). However, MGCD290 showed synergy or partial synergy for 33.3%, 30.1%, 36.7%, and 80.0% of the isolates when tested with anidulafungin, caspofungin, micafungin, and fluconazole, respectively. Favorable interactions were achieved with low concentrations of MGCD290 (0.015-0.25 μg/mL), and categorical shifts were observed in 2 of 8 (25.0%) isolates of C. albicans and 2 of 3 (66.7%) isolates of C. krusei and in 4 of the 5 (80.0%) fluconazole-resistant isolates of C. glabrata. MGCD290 exerts a distinctly favorable influence on the MICs of fluconazole and the echinocandins, resulting in conversion from resistance to susceptibility regardless of fks mutations.