Rearrangements involving the RET gene are common in radiation-associated papillary thyroid cancer (PTC). TheRET/PTC1 type of rearrangement is an inversion of chromosome 10 mediated by illegitimate recombination between the RETand the H4 genes, which are 30 megabases apart. Here we ask whether despite the great linear distance between them, RETand H4 recombination might be promoted by their proximity in the nucleus. We used two-color fluorescence in situ hybridization and three-dimensional microscopy to map the positions of the RETand H4 loci within interphase nuclei. At least one pair ofRET and H4 was juxtaposed in 35% of normal human thyroid cells and in 21% of peripheral blood lymphocytes, but only in 6% of normal mammary epithelial cells. Spatial contiguity ofRET and H4 may provide a structural basis for generation of RET/PTC1 rearrangement by allowing a single radiation track to produce a double-strand break in each gene at the same site in the nucleus.