We report a method for the sensitive detection of rare chromosome breaks and translocations in interphase cells. HiBA-FISH (High-throughput break-apart FISH) combines high-throughput imaging with the measurement of the spatial separation of FISH probes flanking target genome regions of interest. As proof-of-principle, we apply hiBA-FISH to detect with high sensitivity and specificity rare chromosome breaks and translocations in the anaplastic large cell lymphoma breakpoint regions of NPM1 and ALK. This method complements existing approaches to detect translocations by overcoming the need for precise knowledge of translocation breakpoints and it extends traditional FISH by its quantitative nature.