OBJECTIVE To report a case of reversible left posterior fascicular block (LPFB) associated with high-dose interleukin-2 (IL-2) therapy. METHODS A 50-year-old white, nonsmoking male with a history of hypertension, hyperlipidemia, paroxysmal atrial fibrillation, and hypothyroidism had been recently diagnosed with metastatic clear cell-type renal cell carcinoma. He was started on high-dose IL-2 therapy (600,000 IU/kg/dose by 15-min intravenous infusion every 8 h for up to 14 consecutive doses over 5 days, as tolerated). He developed new-onset LPFB after the second dose of IL-2, which was diagnosed electrocardiographically with right axis deviation; deep S waves in lead I; and qR waves in leads II, III, and aVF. He denied chest pain, palpitations, or syncope. The LPFB resolved 18 hours after discontinuation of IL-2 without any potential complications or delay of hospital discharge. The patient completed 9 of 14 doses of IL-2 therapy. Similar electrocardiogram changes were noticed during 2 subsequent cycles of high-dose IL-2 treatment, both of which resolved spontaneously. CONCLUSIONS High-dose IL-2 is a Food and Drug Administration-approved biological agent used as monotherapy for the treatment of metastatic renal cell carcinoma and metastatic melanoma. Capillary leak syndrome has been associated with IL-2 therapy and many of its cardiac and noncardiac toxicities. In our patient, LPFB was observed as a reversible adverse reaction to high-dose IL-2 therapy. The Naranjo probability scale indicates a probable relationship between LPFB and high-dose IL-2 in this patient. LPFB has not previously been reported as an adverse reaction associated with high-dose IL-2 therapy. CONCLUSIONS LPFB may be a reversible cardiac complication associated with high-dose IL-2 therapy. Healthcare professionals should be aware of this potential adverse effect.