Flucytosine (5-FC) monotherapy for cryptococcosis is not advocated because drug resistance emerges during therapy. Reported documentation of this widely accepted belief is surprisingly scarce. Therefore, we reviewed our experience with 5-FC monotherapy for 27 patients treated between 1968 and 1973. Patients were selected on the basis of criteria associated with good prognosis. In this group, 5-FC monotherapy resulted in cure in eight cases and improvement in two. Overall, response was seen in 10 (43%) of 23 evaluable patients. Therapy failed for 13 patients, including 5 who relapsed, 2 who had partial responses, and 6 without response. Resistance was noted to have developed in isolates from six (50%) of 12 patients for whom therapy failed. Although the 57% failure rate associated with 5-FC alone precludes its use as monotherapy, our study did show that this treatment was well tolerated and that failure was not invariably associated with development of resistance.