CGH analyses of human tumors have revealed that chromosomal aberrations result in genomic imbalances specific for different tumor from diverse tissue types. Furthermore, these changes define discrete steps in the progression of epithelial tumors. More than 90% of cervical carcinomas carry extra copies of chromosome 3, which results in the genomic amplification of the human telomerase gene TERC. It is therefore logical to apply the visualization of these recurring and specific chromosomal aberrations to complement and enhance the cytomorphological diagnosis of human cancers and their precursor lesions. This can be achieved using interphase cytogenetics with fluorescently tagged DNA probes that recognize specific chromosomal target regions directly in interphase cells. The application of this genetic test to routinely collected cytological specimens proved that high-grade intraepithelial lesions (HSIL, which are comprised of CIN2 and CIN3) could be discerned from normal samples, ASCUS and low-grade intraepithelial lesions (LSIL, or CIN1) with a sensitivity and specificity exceeding 90%, independent of the cytomorphological assessment. In order to explore whether gain of 3q and genomic amplification of hTERC increases the propensity of progression from LSIL to HSIL and invasive carcinoma, we have applied the probe set to a series of previously stained PAP-smears. The samples included (i) CIN1 and CIN2 lesions that progressed to CIN3, (ii) CIN1 and CIN2 lesions that regressed spontaneously, and (iii) normal PAP-smears from women who subsequently developed CIN3 or cervical cancer. Our data suggest that genomic amplification of hTERC is required for the transition from CIN1 and CIN2 to CIN3 and that it predicts progression. Of note, hTERC amplification was found in 30% of cytologically normal PAP-smears from women who were diagnosed with CIN3 or invasive cervical carcinomas after a short latency. We conclude that the detection of genomic amplification of hTERC in routinely collected PAP-smears can assist in identifying low-grade lesions with a high progression risk and in reduction of false negative individual cytological screenings.