Careful selection and treatment monitoring of patients with gestational trophoblastic tumors (GTT) is critical because 20 - 50% of patients may develop a resistance and consequently require alternative chemotherapeutic agents. In our study we propose and demonstrate the efficacy of etoposide (VP16) as a second-line drug. An average of 5 courses with VP16 were used to achieve a remission in 12 patients resistant to MTX with low-risk GTT. Toxicity was mild and no resistance to VP16 was observed. A follow-up of 66 months (range, 22-109) has been performed for the patients and all of them are now disease free. Two patients had a pregnancy, respectively, 3 and 4 years after treatment. The others did not desire any pregnancy.