Amphotericin B (AmB) is a potent antifungal polyene macrolide antibiotic and is the drug of choice for the treatment of deep-seated mycotic infections. Its use is limited, owing to its nephrotoxicity, and it must be dispersed in deoxycholate for parenteral administration. In contrast, AME (the monomethyl derivative of AmB) is water dispersible, is appreciably less cytotoxic than AmB toward a variety of cell types, and is reportedly active against the acquired immunodeficiency syndrome virus (human immunodeficiency virus type 1). The latter activity has generated interest in AME as an antiviral drug. However, AME is perceived to be neurotoxic, based on the outcome of a human clinical trial of AME as an antifungal drug. AmB is not regarded as neurotoxic, presumably because any neurotoxicity in vivo is precluded by its nephrotoxicity. It was inportant, therefore, to determine the potential for neurotoxicity of the two agents in comparative tests, assessing the effects of their direct action against neural cells in culture. Rat cortical cells, comprising astrocytes and oligodendrocytes, were used. AME was at least 10 times less toxic than AmB and equally less toxic against several other nonneural cell types also included in these tests. Equally important, AmB disrupted the myelin sheath in these cultures, and it inhibited its generation. AME did not, even at a concentration 10 times greater than the toxic concentration of AmB. AmB is, therefore, potentially more neurotoxic than AME, contrary to current perception. AME is effective as an antifungal and antiviral drug at a concentration far below its toxic concentration for neural cells. Also, AME does not cross the blood-brain barrier appreciably, so that a therapeutic level in blood can be expected without encountering neurotoxicity.Amphotericin B (AmB), as the sodium deoxycholate complex (Fungizone), is the drug of choice for the treatment of deep-seated mycotic infections. The therapeutic index for this drug is relatively low, with multiple, although rare, adverse reactions to the nervous system. Alterations in hearing and vision, headaches, convulsions, and drowsiness, etc., have long been seen as adverse neurological side effects of parenteral AmB therapy (20, 23). Symptoms of major neuropsychiatric disorders after intravenous therapy have also been associated with myelin degeneration seen in peripheral nerve sections (8). Intrathecal AmB therapy, particularly, has been associated with acute febrile meningeal reactions (9), toxic delirium and electroencephalograph abnormalities (18,21,22), and myelopathy (3, 4).The methyl ester derivative of AmB (AME) has a similar spectrum of action against fungal infections (1). Moreover, studies of acute toxicity in animals indicated that AME is significantly less toxic than AmB.There is an urgent need for new antiviral drugs that are effective against the acquired immunodeficiency syndrome. Both AME and AmB are active against human immunodeficiency virus type 1 and against virus-infected cells (19; 0.