The ataxia telangiectasia mutated (ATM) gene is a tumor suppressor gene that plays a critical role in cell cycle arrest, apoptosis, and DNA repair. We evaluated two reported nonsynonymous SNPs (rs1800054 and rs1800058) and three additional common gene variants (rs664143, rs228589, rs1003623) in the ATM gene in relation to breast cancer risk. A two-stage case-control study, using data from the Shanghai Breast Cancer Study, was conducted in which all SNPs were screened in the stage I study, including 1,123 cases and 1,232 controls. Any promising associations were re-evaluated in the stage II study, including 2,003 cases and 1,918 controls. In the stage I study, with the exception of rs1003623, no apparent association was found for any other SNPs with breast cancer risk. For the rs1003623, the T allele was associated with an increased breast cancer risk among postmenopausal women with odds ratios (ORs) of 1.4 (95% Confidence Intervals (CIs) = 1.0-1.9) for the CT and 1.6 (95% CIs = 1.0-2.4) for the TT, (P for trend = 0.03). This association, however, was not replicated in the stage II study, suggesting that the positive association identified in stage I for rs1003623 may be due to chance. Our study reveals no apparent association of common ATM variants with breast cancer risk and underscores the importance of replication using independent samples to reduce type I errors in association studies of low-penetrance genetic factors.