OBJECTIVE: To assess toxicity and efficacy of weekly high-dose methotrexate-etoposide (HD MTX-ETO) in high-risk gestational trophoblastic neoplasia (GTN). METHODS: Retrospective chart review of high-risk GTN patients treated with HD MTX-ETO (methotrexate 1000mg/m² day 1, etoposide 100mg/m² days 1 and 2, q 1wk). RESULTS: 134cycles of HD MTX-ETO were administered to twelve patients; median number of cycles was 8 (range 2-39cycles). Median follow up was 25.5months (range 11-69). 7 of these patients switched due to ototoxicity from EP-EMA (etoposide 150mg/m², cisplatin 75mg/m² i.v. day 1; etoposide 100mg/m², methotrexate 300mg/m², dactinomycin 0.5mg i.v. day 8, q 14d) to HD MTX-ETO, after an average of 7cycles of EP-EMA. Six achieved complete remission without disease recurrence. One patient with a placental site trophoblastic tumour died due to progressive disease. Five patients received HD MTX-ETO primarily; 1 patient with choriocarcinoma presenting with metastases to the brain and liver (WHO score 19) was switched to EP-EMA and died due to complications under EP-EMA. The other 4 achieved complete remission without disease recurrence. HD MTX-ETO was well tolerated; non-haematological toxicity was low except for alopecia and fatigue. Nine patients had grade 2-4 anaemia and received packed cells. Eight patients had grade 3-4 neutropenia and received G-CSF. Two patients developed febrile neutropenia without sepsis. CONCLUSIONS: These preliminary results show a better toxicity profile with HD MTX-ETO than EP-EMA and encouraging efficacy. HD MTX-ETO might be a treatment option for some patients with high-risk GTN and needs further investigation.