The use of isotretinoin (13-cis-retinoic acid) in the treatment of numerous dermatologic disorders, as well as the side effects encountered with use of the drug, have increased remarkably since its release. We encountered a case of Staphylococcus aureus endocarditis in a patient with chronic stable aortic insufficiency undergoing therapy with isotretinoin for extensive actinic keratoses. Although significant dysfunction of the immune system has not been demonstrated with isotretinoin, nasal colonization with S aureus has been shown to occur. Changes in skin fragility caused by the drug may provide a portal of entry for the organism. Physicians should be alert for this potential complication in patients with an underlying cardiac valvular lesion; antibiotic prophylaxis may be indicated in this group during isotretinoin therapy.