In recent years, systemic and intralesional interferons (IFNs) have been used successfully to treat a variety of skin tumours including T-cell lymphoma, malignant melanoma, Kaposi's sarcoma and basal cell carcinoma. However, only a few studies have been reported on the use of IFN for the treatment of squamous cell carcinoma (SCC). The aim of this study was to evaluate the efficacy of intra and perilesionally administered IFNα-2a on SCC. A group of 36 patients with SCC ranging in size from 1.5 to 4 cm were treated with intra- and perilesional recombinant IFNα-2a. The doses varied from 1.5 to 3£106IU, three times a week for periods of 4–8 weeks. Complete response (CR) was achieved in 25 of 36 patients (69.5%) partial response in 7 patients (19.5%) and no response in 4 patients (11%). Side-effects including fever, headache and mild fatigue were observed during the first injection in 9 patients (25%). However, they were completely reversible with the use of paracetamol. After follow-up periods of 12–48 months (mean 30 months) no recurrence was noted. The present study demonstrates that intra and perilesional IFNα-2a can be considered an effective and safe therapy for SCC.