Hydrophobins are small surface-active fungal proteins that self-assemble into amphipathic monolayers at hydrophobic-hydrophilic interfaces. The amphipathic nature and self-assembly properties of hydrophobins render these proteins uniquely suited to encapsulation and solubilization of hydrophobic drugs. Amphotericin (AmB) is a poorly soluble and aggregation-prone drug that is used to treat serious fungal infections. The insolubility of AmB in aqueous environments and its binding to cholesterol leads to its high toxicity and can cause severe side effects that include chills, fever, headache, and nausea. Hence there is a need for strategies to increase the solubility of AmB enabling decreased drug dosages, thereby reducing toxicity-related side effects. To assess if the addition of hydrophobins increases AmB solubility, the hydrophobin proteins EAS and DewY were recombinantly produced and tested each in combination with AmB. Characterization of the solubility of the AmB in the presence of the hydrophobins confirmed that both EAS and DewY increase the solubility of AmB. Furthermore, testing of the combinations against the model yeast Saccharomyces cerevisiae demonstrate that the addition of the hydrophobins reduced the amount of AmB required to inhibit growth of the fungus. DewY was found to be more synergistic with AmB than EAS. Overall, these preliminary data demonstrate the potential of utilizing hydrophobin proteins for the development of novel combination antifungal therapies.