AbstractBackground and AimsLeisure sedentary behavior (LSB) is associated with the risk of cancer, but the causal relationship between them has not been clarified. The aim of this study was to assess the potential causal association between LSB and risk of 15 site‐specific cancers.MethodsThe causal association between LSB and cancer were assessed with univariate Mendelian randomization (UVMR) and multivariate Mendelian randomization (MVMR). 194 SNPs associated with LSB (from the UK Biobank 408,815 individuals) were adopted as the instrument variables. Sensitivity analyses were performed to ensure the robustness of the results.ResultsUVMR analysis revealed that television watching significantly increased the risk of endometrial cancer (OR = 1.29, 95% CI = 1.02–1.64,p= 0.04) (mainly the endometrioid histology [OR = 1.28, 95% CI = 1.02–1.60,p= 0.031])，breast cancer (OR = 1.16, 95% CI = 1.04–1.30,p= 0.007) (both ER+ breast cancer [OR = 1.17, 95% CI = 1.03–1.33,p= 0.015], and ER− breast cancer [OR = 1.55, 95% CI = 1.26–1.89,p= 2.23 × 10−5]). Although causal association was not found between television watching and ovarian cancer, it was seen in low grade and low malignant potential serous ovarian cancer (OR = 1.49, 95% CI = 1.07–2.08,p= 0.018). However, significant results were not obtained in the UVMR analysis between driving, computer use and the 15 types of cancer. Further MVMR analysis indicated that the above results are independent from most metabolic factors and dietary habits, but mediated by educational attainment.ConclusionLSB in form of television watching has independent causal association with the risk of endometrial cancer, breast cancer, and ovarian cancer.