A 58-year-old woman who had been taking digoxin 0.25 mg/day for more than 35 years for heart palpitations after mitral valve repair was prescribed a 5-day course of telithromycin for acute bronchitis. On the sixth day of therapy, she came to the emergency department complaining of general malaise and having experienced three episodes of syncope over the previous 2 days. Laboratory analysis revealed elevated digoxin plasma levels, and electrocardiography showed several nonspecific repolarization anomalies. Telithromycin is known to increase digoxin plasma levels; however, the clinical significance of this interaction is not known. To our knowledge, this is the first report of elevated plasma digoxin levels associated with signs and symptoms of toxicity. This drug interaction-determined as probable according to the Naranjo adverse drug reaction probability scale-may be mediated by P-glycoprotein. By inhibiting the transport of digoxin by P-glycoprotein, telithromycin may have decreased digoxin elimination in the intestinal lumen and its renal tubular excretion, resulting in elevated plasma levels and drug toxicity. Clinicians should be aware of possible digoxin toxicity after concomitant administration with telithromycin, especially in patients who are at risk, such as those with electrolyte abnormalities and decreased renal function.