The in vitro activity of the lipopeptide PAL-Lys-Lys-NH(2) (PAL), alone or combined with either fluconazole (FLU) or amphotericin B (AMB), was investigated against 14 Cryptococcus neoformans isolates. PAL MICs ranged from 1.0 to 4.0 microg/ml. Fungicidal activity was observed. Synergy, defined as a fractional inhibitory concentration (FIC) index of < or =0.5, was observed in 21.4% of PAL/AMB interactions. Antagonism (FIC index>4) was never observed. The broad antifungal activity and the positive interactions with AMB suggest that PAL can represent a promising candidate in infections due to C. neoformans.