We evaluated the effect of multiple treatment- and disease-related variables on the outcome of patients receiving whole-brain radiation therapy (WBRT) for metastatic gestational trophoblastic disease (GTD). Between November 1967 and December 1994, 21 patients were treated at our institution for GTD metastatic to the brain. All received WBRT, of median 2200 cGy (range 200-3600 cGy). Median follow-up, from date of diagnosis of brain metastases, was 77 months (range 11-170 months). The 5-year actuarial local control of initial brain metastases with > or = 2200 cGy was 91%, compared to 24% with < 2200 cGy (P = 0.05). The 2- and 5-year actuarial survivals of the 9 patients whose disease was controlled at extracranial sites were 100 and 83%, respectively, compared to 8 and 0%, respectively, for the 12 whose extracranial disease was not controlled (P = 0.0002). Four (33%) of the patients with persistent or progressive extracranial disease later developed new sites of brain metastases, compared to 0% of the patients whose extracranial disease was controlled (P = 0.05). Eleven patients progressed at their initial site(s) of brain metastasis or developed new intracranial lesions; 6 of them died of brain metastases. Survival of patients with GTD metastatic to the brain is excellent if extracranial disease can be controlled. The total dose of radiation is critical in achieving control of initial brain metastases. Patients with uncontrolled extracranial disease are more likely to develop new brain metastases. Salvage of intracranial failures after WBRT is rare.