Two-color fluorescence in situ hybridization (FISH) analysis using human chromosome arm-specific telomeric probes (telomeric probes) was used successfully to detect each derivative chromosome of a translocation carrier in five couples who requested a prenatal diagnosis in future pregnancies. Most of the human chromosome terminal bands are G-band-negative, and even FISH analysis using whole-chromosome painting (wcp) probes are often of insufficient complexity to detect subtle chromosomal changes. A complete set of human telomeric probes was developed to improve the sensitivity of diagnosis of microdeletions or other cryptic rearrangements in telomeric regions. Two-color telomeric FISH was the only possible method for precise prenatal diagnosis of one of the couples, because the carrier's chromosomal aberration was too subtle to be detected by wcp FISH or conventional methods. We have demonstrated that two-color telomeric FISH has the potential to be a powerful new tool in the detection of cryptic chromosomal rearrangements involving telomeric regions in prenatal diagnosis precisely and in time.