Erlotinib, an epidermal growth factor receptor (EGFR) inhibitor, may have off-target activity inducing acute myeloid leukemia (AML) differentiation, possibly through SYK inhibition. We investigated erlotinib in a pilot phase II study for efficacy in relapsed/refractory AML patients at a dose of 150 mg once daily in 28-day cycles. Twenty-nine patients were treated for a median of 29 days (range 12–142 days). Seven patients (24%) received > 1 cycle of therapy and 12 (41%) discontinued treatment before day 28 due to disease progression. One patient (3%) achieved complete remission and 2 (7%) a > 50% reduction in blasts. The most common toxicities associated with erlotinib were fatigue in 10 patients (34%), diarrhea in 10 (34%), nausea in 8 (28%), and rash in 7 (24%). Only 2 patients (7%) had study drug-related adverse events requiring dose reductions and eventual discontinuation. The main reason for treatment discontinuation was disease progression in 26 patients (90%). All patients had died by the time of the last follow-up. Progression of disease was the primary cause of death in all patients. Median overall survival was 14 weeks (range 2.3–96.9 weeks) and median event-free survival was 5 weeks (range 1.7–21.0 weeks). Erlotinib as a single agent has limited clinical efficacy in patients with relapsed/refractory AML.