Background There is an inverse relationship between febrile infection and the risk of malignancies. Interferon gamma (IFN-[gamma]) plays an important role in fever induction and its expression increases with incubation at fever-range temperatures. Therefore, the genetic polymorphism of IFN-[gamma] may modify the association of febrile infection with breast cancer risk. Methodology and Principal Findings Information on potential breast cancer risk factors, history of fever during the last 10 years, and blood specimens were collected from 839 incident breast cancer cases and 863 age-matched controls between October 2008 and June 2010 in Guangzhou, China. IFN-[gamma] (rs2069705) was genotyped using a matrix-assisted laser desorption/ionization time-of-flight mass spectrometry platform. Odds ratios (OR) and 95% confidence intervals (CIs) were calculated using multivariate logistic regression. We found that women who had experienced [greater than or equal to]1 fever per year had a decreased risk of breast cancer [ORs and 95% CI: 0.77 (0.61-0.99)] compared to those with less than one fever a year. This association only occurred in women with CT/TT genotypes [0.54 (0.37-0.77)] but not in those with the CC genotype [1.09 (0.77-1.55)]. The association of IFN-[gamma] rs2069705 with the risk of breast cancer was not significant among all participants, while the CT/TT genotypes were significantly related to an elevated risk of breast cancer [1.32 (1.03-1.70)] among the women with Conclusions Our findings indicate a possible link between febrile acute infection and a decreased risk of breast cancer, and this association was modified by IFN-[gamma] rs2069705.