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Spontaneous mutants of Candida albicans resistant to 5-fluorocytosine (5-FC) were isolated from a strain susceptible to 5-FC. These mutants were compared with 5-FC-resistant strains of C. albicans and Torulopsis glabrata isolated from patients treated with the drug and from untreated patients. Resistance to 5-FC was in all cases followed by a decreased susceptibility to 5-fluorouracil. Most strains were also more resistant to 5-fluorouridine and had a lowered incorporation of uridine. In one spontaneous mutant totally resistant to all three 5-fluoropyrimidines, the uridine monophosphate pyrophosphorylase activity was greatly decreased. The 5-FC-resistant strains were of two main phenotypic classes. Class one was unaffected by 5-FC at the highest concentration tested. The growth rate of strains belonging to the other class was markedly decreased by low concentrations of 5-FC, but these strains were still able to form colonies after 7 days of incubation on plates containing very high concentrations of the drug (2,000 mug/ml). The frequency of spontaneous mutation of a susceptible strain to 5-FC resistance was fairly high. The number of mutants growing on media containing 5-FC was unchanged by concentrations ranging from 25 to 500 mug/ml.