Multiple hemangioblastomas (HBs) of the central nervous system (CNS) and retina are associated with von Hippel-Lindau disease (VHL) and also predispose individuals to renal cell carcinomas and visceral cysts. In VHL, microsurgery or radiosurgery cannot prevent new HBs from arising in the CNS or coagulation of retinal HBs. Multiple but thus far asymptomatic HBs pose a therapeutic problem. IFN-alpha-2a has antiangiogenic activity with an especially favorable effect on life-threatening hemangiomas of the liver in children. This is the first study to assess the efficacy of IFN-alpha-2a in treatment of asymptomatic HBs of the CNS and retina. Four patients (three with VHL) with a combined total of 15 HBs of the CNS, 3 HBs of the retina, and 14 renal and 2 pancreatic cysts were treated with s.c. IFN-alpha-2a for 12 months at 3 x 10(6) IU, 3 times/week. Baseline workup consisted of detailed neurological, ophthalmological, and radiological examinations. Follow-up studies at 3, 13, and 21 months were used to monitor the response. No de novo HBs were detected during the therapy, but one appeared 9 months after cessation of IFN-alpha-2a therapy. HBs of the CNS did not shrink markedly during the therapy. IFN-alpha-2a may decrease blood flow in HBs as suggested by shrinkage and diminished leakage of two retinal HBs. However, the therapy did not prevent visceral cysts from growing. The systemic response was also monitored by measurement of serum levels of vascular endothelial growth factor and erythropoietin, which remained essentially unchanged during the treatment. No serious side effects were recorded.