Background Mammalian inositol 1,4,5‐trisphosphate receptor (ITPR) genes encode ubiquitously expressed endoplasmic reticulum Ca2+ channels that have recently been shown to be closely linked to the pathogenesis of several cancers. However, few studies to date have explored associations between ITPR gene family single nucleotide polymorphisms (SNPs) and breast cancer risk. Methods In the present case–control study, 12 SNPs in the potential functional regions of the ITPR1, ITPR2, and ITPR3 genes were genotyped using an Illumina Infinium® Beadchip in 2095 Chinese women (1032 cases and 1063 controls). Results Multivariate logistic regression analyses indicated that a missense SNP in the ITPR3 coding region (rs2229642) was significantly related to breast cancer risk when using an additive model in this study (rs2229642‐adjusted odds ratio = 1.40, 95% confidence interval = 1.12–1.74, p = 2.97 × 10−3). Expression quantitative trait loci analyses indicated that the SNP rs2229642 was associated with reduced ITPR3 expression levels (p = 3.2 × 10−7) and with marked reductions in the expressions of several proximal genes, including BAK1, GRM4, HLA‐DOB, and UQCC2 (p = 0.013, 0.018, 3.4 × 10−3, 3.8 × 10−5), suggesting that it may further regulate other genes associated with oncogenic susceptibility. Kaplan–Meier analyses indicated that the patients with higher ITPR3 expression exhibited significantly poorer outcomes compared to the patients with lower expression of this gene (hazard ratio = 1.11, 95% confidence interval = 1–1.23, p = 0.046). Conclusions The results indicated that genetic variant in the coding region of ITPR3 gene may regulate the expressions of its host and some other cancer‐related genes, as well as act as potential predictive biomarker for susceptibility to breast cancer in the Chinese population.