In mammalian cells, the repair of DNA double-strand breaks (DSBs) is mainly mediated by DNA non-homologous end joining. DNA-dependent protein kinase (DNA-PK), a nuclear serine-threonine kinase and a member of the phosphaditylinositol-3 kinase-related kinase family that is activated by DSBs, is a key component of this pathway. Wortmannin (WM) is known to be an irreversible and potent inhibitor of DNA-PK and has thus been proposed as an effective sensitizer for ionizing radiation and for radiomimetic compounds. The present study, using the cytokinesis block micronucleus assay, reports on the differential effect of WM on the repair of the DNA damage induced by low LET ((60)Co gamma-radiation) and high LET radiation by the boron neutron capture reaction (alpha and Li particles) in V79 Chinese hamster cells. Significant increases in the number of micronuclei per binucleated cell as well as in the frequency of micronucleated binucleated cells were observed in the presence of different concentrations of WM for high LET radiation from the boron neutron capture reaction. The increases observed reached a maximum of approximately 2-fold in comparison with the respective controls. WM, however, had a more pronounced effect on (60)Co gamma-radiation-induced micronuclei, increasing the genotoxic damage from this radiation by approximately 3- to 4-fold. These results are in general in agreement with the concept that DSBs induced by high LET radiation are not a more suitable substrate for the end joining processes mediated by DNA-PK, yet they do not preclude a role for DNA-PK in high LET-induced damage repair.