The present study reports the effects of repeated administration of two different doses of recombinant (r) Interleukin-2 (IL-2) around tumor-draining lymph nodes in 22 patients with recurrent squamous cell carcinoma of the head and neck (HNSCC). Each patient was randomly assigned a dose of 500 or 500,000 IU/r-IL-2/day. Inoculation was made at a depth of 15 mm in the anterior margin of the sternocleidomastoid muscle at 15 mm from its insertion into the mastoid. The injections were made on the same side as the recurrent tumor when draining lymph nodes were still present and contralaterally when only contralateral lymph nodes were present. The 10 daily injection were followed by an interval without treatment until day 40. A further three courses of 10 injections were made at thirty-day intervals in the absence of a CR. There was no toxicity. One complete response (CR) and 2 partial responses (PR) were observed in the 11 patients who received 500 U of IL-2, whereas the higher dose was not effective. The CR was recorded in the 4 patients with an oropharyngeal recurrence. One PR was obtained in the 4 patients with hypopharyngeal recurrences and one in 3 with oral cavity recurrences. Clinical responses were nearly always preceded by improvement of the functional impairment caused by tumour infiltrations of the upper respiratory-digestive organs. The responses lasted 3-5 months and additional courses of 10 injections of IL-2 had no further effects.