The synergism of 5-FC with 4 polyene antibiotics, amphotericin B (amph. B), candicidin, trichomycin and nystatin were investigated in 3 in vitro models measuring the fungistatic and fungicidal activity as well as the development of resistant mutants. In these 3 models candicidin and trichomycin exerted a higher synergistic effect than amph. B or nystatin. In vivo (systemic treatment of septicemic candidiasis of the mouse) the combination of 5-FC with amph. B was, however, the most effective. Only with this combination a complete cure (culturally negative) was observed. For topical treatment of Candida vaginitis in rats, the combination of 5-FC with candicidin proved the most active. As far as the biochemical basis of synergism is concerned in Candida albicans in the presence of polyene antibiotics, the incorporation of fluorinated pyrimidines was increased and the reduction of uptake of histidine by 5-FC alone, significantly enhanced. These effects could not be observed in Cryptococcus neoformans. The release of amino acids, phosphate and potassium caused by polyenes was significantly more pronounced in cells pretreated with 5-FC. Thus, the interaction between 5-FC and the polyenes may, in fact be, mutual.