To comprehensively evaluate the etiological role of ABO blood group in human cancer, we conducted a large-scale meta-analysis of 127 publications totaling 20 million participants including 231 737 patients of 20 cancers, supplemented by genetic evidence. Effects of A, AB and B groups on cancer risk were investigated by respectively comparing with O group and their combined counterparts, and subgroup analysis by ethnicity was conducted for O-referent models. For cancer categories, A group increased risk of cancers of oral cavity and nasopharynx, digestive and female genital organs, while both AB and B groups showed associations with cancers of digestive and female genital organs. For individual cancers, A group significantly increased the risk of nine cancers including oral cavity (OR = 1.17, P = .013), stomach (OR = 1.19, P = 3.90 × 10-15 ), pancreas (OR = 1.33, P = 9.89 × 10-33 ), colorectum (OR = 1.09, P = .001), liver (OR = 1.23, P = .011), ovary (OR = 1.13, P = .001), cervix (OR = 1.17, P = .025), bladder (OR = 1.12, P = .025) and breast (OR = 1.06, P = .043). AB group showed associations with only three cancers: stomach (OR = 1.10, P = .007), pancreas (OR = 1.21, P = .001) and ovary (OR = 1.28, P = .006). B group, except for shared associations with A group on pancreas (OR = 1.20, P = 2.27 × 10-5 ) and cervix cancers (OR = 1.13, P = .011), had two distinct associations with esophagus (OR = 1.17, P = .002) and nonmelanoma skin cancers (OR = 0.96, P = .017). Ethnicity-specific analyses revealed the notable effects of non-O groups on pancreatic cancer both in Caucasians and Asians. In genetic analysis, four SNPs were associated with the risk of pancreatic cancer, with rs505922 corresponding to O group showing the strongest protective effect (P = 1.16 × 10-23 ). Our study provided comprehensive evidence of ABO blood group associated with cancers and highlighted its carcinogenic role.© 2023 UICC.