Radon is a ubiquitous inhaled human carcinogen that is thought to be the largest single natural source of human exposure to radiation. We report that a freely replicating episome in human cells exposed to radon gas underwent mutagenic changes, a high proportion of which were large deletions involving many thousands of base pairs. These deletions were not randomly distributed but started and ended in defined regions as if caused by the passage of a single alpha-particle track through a coiled chromatin structure. The sizes appeared to be defined by structural features of chromatin: the minimum size was 2435 base pairs, and the maximum size was 8051 base pairs, close to the upper limit that would leave intact the plasmid sequences required for selection in bacteria. Ends were rejoined by nonhomologous recombination involving up to 6 base pairs of homology. This process may not be confined to the repair of exogenously induced double-strand breaks but may be used for rejoining free DNA ends generated by a variety of cellular processes. The mechanism of alpha-particle deletion mutagenesis may account for the high relative biological effectiveness of radon irradiation for many end points and its consequences for lung carcinogenesis.