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Background: Asbestos induces DNA and chromosomal damage, but the DNA repair pathways protecting human cells against its genotoxicity are largely unknown. Polymorphisms in XRCC1 have been associated with altered susceptibility to asbestos-related diseases. However, it is unclear whether oxidative DNA damage repaired by XRCC1 contributes to asbestos-induced chromosomal damage. Objectives: We sought to examine the importance of XRCC1 in protection against genotoxic effects of crocidolite and Libby amphibole asbestos. Methods: We developed a genetic model of XRCC1 deficiency in human lung epithelial H460 cells and evaluated genotoxic responses to carcinogenic fibers (crocidolite asbestos, Libby amphibole) and nongenotoxic materials (wollastonite, titanium dioxide). Results: XRCC1 knockdown sensitized cells to the clastogenic and cytotoxic effects of oxidants [hydrogen peroxide (H2O2), bleomycin] but not to the nonoxidant paclitaxel. XRCC1 knockdown strongly enhanced genotoxicity of amphibole fibers as evidenced by elevated formation of clastogenic micronuclei. Crocidolite induced primarily clastogenic micronuclei, whereas Libby amphibole induced both clastogenic and aneugenic micronuclei. Crocidolite and bleomycin were potent inducers of nuclear buds, which were enhanced by XRCC1 deficiency. Libby amphibole and H2O2 did not induce nuclear buds, irrespective of XRCC1 status. Crocidolite and Libby amphibole similarly activated the p53 pathway. Conclusions: Oxidative DNA damage repaired by XRCC1 (oxidized bases, single-strand breaks) is a major cause of chromosomal breaks induced by crocidolite and Libby amphibole. Nuclear buds are a novel biomarker of genetic damage induced by exposure to crocidolite asbestos, which we suggest are associated with clustered DNA damage. These results provide mechanistic evidence for the epidemiological association between XRCC1 polymorphisms and susceptibility to asbestos-related disease., Editor's Summary Pathways involved in the repair of asbestos-induced DNA damage are largely unknown, but XRCC1 polymorphisms that may influence the efficacy of DNA repair have been associated with susceptibility to asbestos-related diseases. Pietruska et al. (p. 1707) examined the role of XRCC1 in genotoxic effects of crocidolite and Libby amphibole asbestos in normal and XRCC1-deficient human lung epithelial H460 cells. The authors report that oxidative DNA damage, including oxidized bases and single-strand breaks, was increased following asbestos exposure in XRCC1-deficient cells compared with control cells, and was a major cause of chromosomal breaks induced by crocidolite and Libby amphibole. Nuclear buds, a possible marker of clustered DNA damage, were induced by crocidolite asbestos but not Libby amphibole. The authors conclude that their findings provide mechanistic support for epidemiologic evidence linking XRCC1 polymorphisms and susceptibility to asbestos-related disease.