Amphotericin B is well established as a highly efficacious agent against systemic fungal infections in humans. The therapeutic potential of amphotericin B is limited due to its side effects. Although in clinical use for more than 35 years, impairment of liver function is not considered to be a typical adverse effect of amphotericin B. Experimental data suggest that the drug may interfere with the hepatic cytochrome P450 and may thus influence the metabolic capacity of the liver. A confirmation of such a finding in patients treated with amphotericin B would be of value. The incidence of severe acute or subacute hepatotoxicity in response to amphotericin B is very low. Frequently, in critically ill patients, it is not always clear whether liver abnormalities are caused by an antifungal agent or whether they are due to the critical condition of these patients. Nevertheless, there are experimental data suggesting that amphotericin B may influence the metabolic capacity of the liver. Accordingly, drug interactions during prolonged amphotericin B treatment seem possible. Careful monitoring of liver function in those patients receiving amphotericin B in combination with other drugs, which undergo hepatic metabolism or are potentially hepatotoxic, is recommended. In this review, the current understanding and knowledge of the clinical significance, detection, and possible pathogenesis of amphotericin-B-induced liver damage are presented. With respect to the current experimental data, the influence of the drug on the hepatic microsomal cytochrome P450 are also presented and discussed, as is the impact of several clinical studies using different amphotericin B formulas in humans.