Emergence, during therapy, of fungi resistant to amphotericin B is purportedly rare, as fungi with altered cell membrane ergosterol content are considered too fragile to survive normal host defenses. Progressive amphotericin B resistance arose in a strain of Candida tropicalis isolated repeatedly from the urine of a patient with pyelonephritis. The most resistant isolate (R-2) lacked cell membrane ergosterol, the usual attachment site for amphotericin B, and was not inhibited by greater than 500 micrograms/ml of the drug. R-2 infected and killed embryonated eggs, but was unable to produce progressive renal infection in steroid-treated mice because of a reduced capacity to produce pseudomycelia. Persistent infection of the patient by this altered fungus was attributed to defective leukocyte candidacidal activity, especially marked in autologous serum, and to defective Candida-related cell-mediated immunity. A literature review suggests that amphotericin B resistance may not be as rare as many authorities have indicated. It is apparent that few laboratories routinely monitor fungi for amphotericin B susceptibility. In patients with defective antimicrobial defenses, amphotericin B-resistant fungi may survive, produce progressive infection, and require alternative chemotherapy for eradication.