Risk from exposure to energetic heavy ions is considered one of the main problems for human space exploration. Late stochastic risk estimates, particularly cancer, are affected by large uncertainties. Basic cell biology studies to elucidate the mechanisms involved in genetic damage are necessary to reduce the uncertainty and eventually design effective countermeasures. To study the influence of nuclear architecture on the formation of chromosomal rearrangements, normal diploid human fibroblasts have been exposed to heavy ions in horizontal and vertical positions. Analysis of chromosomal aberrations by arm-specific mFISH shows that, at the same radiation dose, the yield of chromosomal damage is modified by the irradiation geometry. A clear difference is seen in the fraction of aberrant cells, owing to the different nuclear cross sections.