OBJECTIVE To analyze the genetic background of tumors in patients with placental site trophoblastic tumors (PSTTs) and clinical outcome in patients treated for this rare variant of trophoblastic disease at a single center. METHODS Analysis of all patients with PSTTs treated at the Charing Cross Hospital between 1975 and 1995. RESULTS We studied the molecular genetics of a group of PSTTs using polymerase chain reaction allelotyping and GeneScan software. We were able to show, in the seven cases in which detailed molecular analysis was successful, that four of these PSTTs were from diploid, bi-parental pregnancies and three were androgenetic tumors following monospermic complete hydatidiform moles. For patients with PSTT localized to the uterus, the treatment of choice is hysterectomy. The sensitivity of PSTT to current cytotoxic chemotherapy is variable. Several patients have been cured using the etoposide, methotrexate, actinomycin D/cyclophosphamide, vincristine schedule, but clinical impressions suggest that cisplatinum probably should be introduced into the chemotherapy schedule from the outset in a schedule such as etoposide, cisplatin/etoposide, methotrexate, actinomycin D. CONCLUSIONS PSTT is a very rare variant of gestational trophoblastic tumor, and its biologic behavior is clearly heterogeneous. The treatment of choice for patients whose disease is limited to the uterus is hysterectomy; for patients with more extensive or metastatic disease, chemotherapy is indicated, but the clinical outcome is variable. A long interval from the antecedent pregnancy to clinical presentation is a major adverse prognostic variable, and the outcome in patients whose last known pregnancy was > 2 years prior to presentation with PSTT is poor.