Two patients experienced hepatotoxicity associated with erythromycin estolate (Ilosone) usage, followed 13 and 15 years later by an hepatotoxic reaction with administration of erythromycin ethylsuccinate (E.E.S.). These cases provide further evidence for erythromycin ethylsuccinate-associated hepatotoxicity and demonstrate erythromycin cross-sensitivity after previous erythromycin estolate liver injury. Hepatotoxicity to both sensitivity after previous erythromycin estolate liver injury. Hepatotoxicity to both estolate and ethylsuccinate preparations of erythromycin stimulates speculation regarding the potentially hepatotoxic moiety of the erythromycin molecule. Furthermore, these cases suggest that all erythromycin preparations should be avoided or used only with careful monitoring in patients with previous erythromycin-associated liver injury.