Complete hydatidiform moles (CHM) are the most common form of gestational trophoblastic disease and a frequent antecedent to choriocarcinoma. Cytogenetic investigations into the origin of these tumors have shown that they can arise by virtue of unusual fertilization events. In this study we used molecular genetic "fingerprinting" methods to examine the genome of 22 consecutive CHM in order to determine their derivation. We found that 60% contained alleles consistent with a completely homozygous androgenic origin. The remaining 40% were heterozygous for marker alleles; half of these were completely androgenic in origin. The other half of these heterozygous CHM contained alleles from the maternal genome, indicating a biparental contribution. These findings suggest that the pathogenesis of CHM is more heterogenous than previously suspected, and can arise from biparental fertilization events. In addition, we found that mutations occur frequently at many loci in these tumors, which may reflect a generalized genetic instability perhaps related to subsequent malignant change. Thus, molecular genetic analysis of CHM provides new insights into the genesis of CHM and will be a powerful method for understanding their clinical biology.