Background: For decades, studies have been performed to evaluate the association between ABO blood groups and risk of cancer. However, whether ABO blood groups are associated with overall cancer risk remains unclear. We therefore conducted a meta-analysis of observational studies to assess this association. Materials and Methods: A search of Pubmed, Embase, ScienceDirect, Wiley, and Web of Knowledge databases (to May 2013) was supplemented by manual searches of bibliographies of key retrieved articles and relevant reviews. We included case-control studies and cohort studies with more than 100 cancer cases. Results: The search yielded 89 eligible studies that reported 100,554 cases at 30 cancer sites. For overall cancer risk, the pooled OR was 1.12 (95%CI: 1.09-1.16) for A vs. non- A groups, and 0.84 (95%CI: 0.80-0.88) for O vs. non-O groups. For individual cancer sites, blood group A was found to confer increased risk of gastric cancer (OR=1.18; 95%CI: 1.13-1.24), pancreatic cancer (OR=1.23; 95%CI: 1.15-1.32), breast cancer (OR=1.12; 95%CI: 1.01-1.24), ovarian cancer (OR=1.16; 95%CI: 1.04-1.27), and nasopharyngeal cancer (OR=1.17; 95%CI: 1.00-1.33). Blood group O was found to be linked to decreased risk of gastric cancer (OR=0.84; 95%CI: 0.80-0.88), pancreatic cancer (OR=0.75; 95%CI: 0.70-0.80), breast cancer (OR=0.90; 95%CI: 0.85-0.95), colorectal cancer (OR=0.89; 95%CI: 0.81-0.96), ovarian cancer (OR=0.76; 95%CI: 0.53-1.00), esophagus cancer (OR=0.94; 95%CI: 0.89-1.00), and nasopharyngeal cancer (OR=0.81; 95%CI: 0.70-0.91). Conclusions: Blood group A is associated with increased risk of cancer, and blood group O is associated with decreased risk of cancer.