BACKGROUND The current randomized, multicenter, Phase III trial was conducted to determine whether the disease free interval and overall survival of patients with T2–T4,N0–N3,M0 squamous cell carcinoma (SCC) of the oral cavity or oropharynx could be extended through the combination of surgery (and radiotherapy, if required) with perilymphatic recombinant IL‐2 (rIL‐2). METHODS Patients with a resectable T2–T4,N0–N3,M0 SCC of the oral cavity and oropharynx were assigned randomly to receive surgery and radiotherapy or to receive IL‐2, surgery, and radiotherapy. Five thousand units of rIL‐2 were injected around the ipsilateral cervical lymph node chain daily for 10 days before surgery. After surgery, contralateral 5‐day rIL‐2 courses were administered monthly for 1 year. The differences in disease free and overall survival between the two groups of patients were evaluated statistically. RESULTS Two hundred two patients finished the study. No significant complications related to rIL‐2 were encountered, and surgery and radiotherapy were not hampered by its prior administration. Multivariate analysis conducted to determine the extent to which survival was influenced by rIL‐2 and the other variables showed that rIL‐2 significantly lengthened disease free survival (P < 0.01) and that this resulted in longer overall survival (P < 0.03). CONCLUSIONS The data emerging from this trial indicate that perilymphatic administration of low, nontoxic doses of rIL‐2 is a simple and manageable way to delay recurrences of SCC. Cancer 2002;95:90–7. © 2002 American Cancer Society. DOI 10.1002/cncr.10654 In patients with resectable squamous cell carcinoma (SCC) of the oral cavity or oropharynx (T2–T4,N0–N3,M0), the perilymphatic administration of low, nontoxic doses of recombinant interleukin 2 (rIL‐2) significantly lengthened disease free survival, resulting in longer overall survival. The regimen of low‐dose rIL‐2 is a simple and manageable way to delay recurrences of oral SCC.