We describe 2 cases of angioblastoma, a rare, destructive pediatric tumor, treated with interferon alfa 2b (IFNalpha2b). The first patient is a 10-month-old male who presented with an ulcerated palatal neoplasm that could not be completely resected. The second is a male neonate with a congenital tumor of the right hand that invaded the hypothenar eminence, destroying the fourth and fifth metacarpals. Biopsy in both patients was interpreted as giant cell angioblastoma. Angioblastoma is rare; there is only 1 reported case that necessitated amputation of an upper extremity, also initially recommended for our patient. Because there is little experience with chemotherapy, permission was granted to employ an antiangiogenic regimen of IFNalpha2b. The angiogenic protein, basic fibroblast growth factor (bFGF), was abnormally elevated in both patients. Both patients received IFNalpha2b. In the first child, it was used after incomplete resection, because biopsy-proven tumor was present at the margin and in the nasopharynx. Biopsies 15 months after initiation of IFN2alphab were negative for tumor. Therapy was stopped after 3 years. Eighteen months later, the patient remains disease-free. In the second child, IFNalpha2b was started after debridement of the ulcerated tumor. Over 11 months, the tumor completely regressed and there was bony regeneration of the metacarpals. The fifth digit was amputated because of damage to the metacarpophalangeal joint by the tumor. IFNalpha2b therapy was discontinued after 1 year of treatment, and the child remains disease-free 2 years and 8 months later. In conclusion, this report demonstrates that: 1) a bFGF-overexpressing low-grade tumor can respond to IFNalpha2b in a manner similar to life-threatening infantile hemangiomas, 2) urinary bFGF levels can help guide IFNalpha dosage in such patients, and 3) although bFGF-mediated tumor angiogenesis is inhibited by IFNalpha, physiologic angiogenesis seems to be unaffected.