Objectives: To determine the risk for recurrent trophoblastic disease after spontaneous normalization of human chorionic gonadotropin (hCG) levels in patients with hydatidiform mole and to determine the risk for tumor relapse after apparent remission following chemotherapy in patients with low- and high-risk persistent trophoblastic disease. Methods: From 1994 until 2004, 355 patients with hydatidiform mole were registered at the Dutch Central Registry of Hydatidiform Mole and were monitored by sequential hCG assays in serum at the department of Chemical Endocrinology of the Radboud University Nijmegen Medical Centre. HCG regression curves were analyzed together with clinical information collected from the Hydatidiform Mole Database. Results: Among the 355 registered hydatidiform mole patients, 265 patients attained spontaneous normalization following evacuation. Of the 265 patients, one patient (0.38%) subsequently required chemotherapeutic treatment for recurrent trophoblastic disease (95% confidence interval 0.0% to 2.1%). HCG levels did not decline to normal (<2.0 ng/ml) are achieved. Our results support the suggestion that two subsequent normal hCG levels may be sufficient to ensure sustained remission after hydatidiform mole evacuation. In contrary, in order to assure sustained remission, the relapse rates after chemotherapy in the current study emphasize the need for surveillance of trophoblastic tumor patients even after complete remission has apparently been achieved.