A Phase II trial in 42 patients with squamous cell cancer of the head and neck (H and NSCC) was performed using a combination immunotherapy with 10-20 days of perilymphatic injections of a natural cytokine mixture (NCM: IRX-2; 200 units IL-2 equivalence) preceded by low dose cyclophosphamide (CY; 300 mg/m(2)) and followed by daily oral indomethacin (25 mg t.i.d.) and zinc (65 mg in a multivitamin preparation). Thirty-nine patients underwent subsequent surgical resection and 22 stage IV patients received additional radiotherapy. Forty-two percent were adjudged to have complete and partial clinical responses (>50% tumor reduction); an additional five patients had minor responses for a total of 58%. Comparison of post-treatment biopsies or surgical specimens showed 90% of patients had reduction in tumor area from 79% to 48% (over half of which was fragmented) and increased area of leukocyte infiltration from 9% to 32% (79% of which was lymphoid). The treatment with IRX-2 was not associated with significant side effects and 24 of patients showed improvement in eating, breathing or phonation or reduced pain and bleeding. Fifteen patients with lymphocytopenia (lymphocyte counts [LC] less than or equal to 1500 mm(3)) showed significant increases in LC, CD3+, CD4+ and CD8+ T lymphocytes of 401, 147, 95 and 100/mm(3), respectively. Analysis of outcome of 32 on protocol patients after 36 months versus 32 concurrent institutional H and NSCC controls showed delayed recurrences and significant increases in mean survival time (MST) and survival (p's<0.02). The data document immunotherapy induced regression of H and NSCC with delayed recurrence and improved mean survival time.