This experience of single agent interferon-alpha treatment in high-grade osteosarcoma was based on observed anti-osteosarcoma activity in laboratory models and was started before introduction of aggressive combination chemotherapy. From 1971 to 1990, 89 consecutive patients with non-metastatic high-grade osteosarcoma received semi-purified, leukocyte interferon-alpha as adjuvant treatment. From 1971 to 1984, 70 patients were given a dose of 3 MIU daily for one month followed by 3 times weekly for an additional 17 months. For 19 patients treated from 1985 to 1990 the dose was increased to 3 MIU daily and the treatment duration extended to 3-5 years. All patients underwent surgery prior to interferon treatment. The toxicity was mainly constitutional and long-term toxicity was virtually absent. With a median follow-up of 12 years the observed 10-year metastases-free and sarcoma specific survival rates were 39% and 43%, respectively. Only one of seven survivors after relapse received chemotherapy. This work suggests activity of interferon-alpha as adjuvant treatment in high-grade osteosarcoma. The efficacy of interferon in combination with standard therapy should be explored in randomized trials.