AbstractFourteen patients with recurrent squamous cell carcinoma of the head and neck (SCCHN) were treated with 10 × 106U of nonrecombinant interferon alpha (IFN) intramuscularly (IM) daily for 3 days every 28 days. There were 11 men and 3 women, with ages ranging from 48 to 74 years. Patients had previously been treated with surgery (9 patients), radiotherapy (13 patients), or chemotherapy (8 patients). All patient had measurable disease by physical exam and radiologic evaluation and a performance status of ⩽2 (ECOG). Patients were treated for a minimum of 3 months and continued on therapy until disease progression. The dose and treatment schedule of IFN was well‐tolerated. Toxicities included low‐grade fever, mild anorexia, and malaise. Treatment was stopped in 1 patient due to the development of atrial fibrillation. One death occurred as a complication of aspiration pneumonia 2 weeks following the onset of therapy and was not felt to be related to IFN therapy. Of the 14 patients treated, there was 1 complete response (30+ months) of a base of tongue primary. Two patients had stabilization of disease (SD, 8 and 12 months). One patient had a mixed response with resolution of subcutaneous nodules. The remaining 10 patients died of progressive disease. Immunoogical assessment was performed on 8 patients. The 1 patient who has a complete response was noted to have markedly low pretreatment natural killer (NK) cell activity and subsequent sharp rise in activity after intial treatment. We conclude that low‐dose cyclic IFN is well‐tolerated in patients with recurrent SCCHN and has potential antitumo