Cryptic subtelomeric chromosome rearrangements play an important role in the aetiology of mental retardation, congenital anomalies, miscarriages and neoplasia. To facilitate a comprehensive molecular-cytogenetic analysis of these extremely gene-rich and mutation-prone chromosome regions, novel multicolour fluorescence in situ hybridisation (FISH) techniques are being developed. As yet, subtelomeric FISH methods have either had limited multiplicities, making it necessary to perform many hybridisations per patient, or a limited scope of analysable chromosome mutation types, thus not detecting some aberration types such as pericentric inversions or very small aberrations. COBRA (COmbined Binary RAtio) labelling is a generic multicolour FISH technique that combines ratio and combinatorial labelling to attain especially high multiplicities with few fluorochromes. The Subtelomere COBRA FISH method ( S-COBRA FISH ) described here detects efficiently all 41 BAC and PAC FISH probes necessary for a complete subtelomere screening in only two hybridisations. It was applied to the analysis of 10 cases with known and partially known aberrations and successfully detected balanced and unbalanced translocations, deletions and an unbalanced pericentric inversion in a mosaic situation. The ability of S-COBRA FISH to efficiently detect all types of balanced and unbalanced subtelomeric chromosome aberrations makes it the most comprehensive diagnostic procedure for human subtelomeric chromosome regions described to date.