© 2014, Society of Surgical Oncology. Purpose: To determine the tolerability and efficacy of long-term treatment with erlotinib for head and neck squamous cell carcinoma after salvage surgery.Methods: An open-label study was conducted of 150 mg of daily erlotinib for 12 months in patients who completed definitive surgical therapy for recurrent head and neck squamous cell carcinoma. The primary outcome measures were tolerability of prolonged erlotinib therapy and disease-free survival and overall survival at 1 and 2 years.Results: Thirty-one patients were enrolled onto this study. Mean duration of erlotinib therapy was 5 months (range 2–374 days), with 8 patients completing the full 12-month course of erlotinib. Of the remaining patients, 8 discontinued therapy as a result of recurrence, 10 for medical or surgical complications deemed unrelated to the study medication, and 3 for drug-related toxicities. There were 25 grade 3 adverse events; 4 were classified as possibly related to study medication. The most common adverse events included acneiform rash (n = 26 patients), fatigue (n = 22), and diarrhea (n = 22). Overall survival was 61 % at 1 year and 56 % at 2 years. Disease-free survival was 54 % at 1 year and 45 % at 2 years. Mean time to recurrence (n = 16) was 8.7 months.Conclusions: Long-term erlotinib is safe and demonstrates some potential survival benefit compared to historical controls. However, despite the absence of grade 3/4 adverse events attributable to the drug, tolerance of long-term erlotinib was a significant barrier to completion of a 12-month course of therapy.