Other ; This is the final version of the article. It first appeared from the Public Library of Science via https://doi.org/10.1371/journal.pmed.1002105 ; Abstract ; $\textbf{Background}$ Observational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors. $\textbf{Methods}$ We applied Mendelian randomization to evaluate the association between BMI and risk of breast cancer occurrence using data from two large breast cancer consortia. We created a weighted BMI genetic score comprising 84 BMI-associated genetic variants to predicted BMI. We evaluated genetically predicted BMI in association with breast cancer risk using individual-level data from the Breast Cancer Association Consortium (BCAC) (cases = 46,325, controls = 42,482). We further evaluated the association between genetically predicted BMI and breast cancer risk using summary statistics from 16,003 cases and 41,335 controls from the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Project. Because most studies measured BMI after cancer diagnosis, we could not conduct a parallel analysis to adequately evaluate the association of measured BMI with breast cancer risk prospectively. $\textbf{Results}$ In the BCAC data, genetically predicted BMI was found to be inversely associated with breast cancer risk (odds ratio [OR] = 0.65 per 5 kg/m$^2$ increase, 95% confidence interval [CI]: 0.56–0.75, $p$ = 3.32 × 10$^{−10}$). The associations were similar for both premenopausal (OR = 0.44, 95% CI:0.31–0.62, $p$ = 9.91 × 10$^{−8}$) and postmenopausal breast cancer (OR = 0.57, 95% CI: 0.46–0.71, $p$ = 1.88 × 10$^{−8}$). This association was replicated in the data from the DRIVE consortium (OR = 0.72, 95% CI: 0.60–0.84, $p$ = 1.64 × 10$^{−7}$). Single marker analyses identified 17 of the 84 BMI-associated single nucleotide polymorphisms (SNPs) in association with breast cancer risk at $p$