OBJECTIVE To test for a significant difference between functional and neoplastic ovarian cyst with respect to epidermal growth factor (EGF) receptor and c-erbB-2 proto-oncogene amplification rates. METHODS We determined amplification of EGF-receptor and c-erbB-2 genes by differential polymerase chain reaction (PCR) on 138 ovarian-cyst aspirates. The semiquantitative differential PCR is based on simultaneous co-amplification of a target gene and a reference gene. Amplification rates were detected by densitometry of silver-stained polyacrylamide gels and were scored as single-, low-, or high-copy numbers. Wilcoxon ranked sum test, Pearson correlation coefficient, and multiple logistic regression were used to evaluate the differences in oncogene amplification and to predict histology. RESULTS There were 71 (51.5%) women with functional cysts, whereas 67 (48.5%) had benign (n = 59) or malignant (n = 8) tumors. Low-copy (two- to fourfold copy numbers) EGF-receptor gene amplification was found in 22 of 67 (33%) women with neoplastic cysts, but in only eight (11%) of those with functional cysts. Neoplastic histology differed significantly from functional histology in correlation to EGF-receptor low-copy gene amplification (r = .279, P < .001). There was no significant difference in c-erbB-2 gene amplification with respect to functional and neoplastic histology (r = .083, P = .32). CONCLUSIONS Low-copy EGF-receptor gene amplification seems to be a market for neoplastic histology. Epidermal growth factor receptor gene amplification may be involved in proliferation and growth in an early stage of tumorigenesis. However, further studies are required to investigate this gene structure abnormality on a gene function level. Amplification of c-erbB-2 proto-oncogene does not appear to be a common factor in the development of ovarian tumors.