OBJECTIVES: To investigate the association between the MTHFR 677C-->T polymorphism and coronary heart disease, assessing small study bias and heterogeneity between studies. DATA SOURCES: Medline and Embase citation searches between January 2001 and August 2004; no language restrictions. STUDY SELECTION: Case-control and prospective studies of association between MTHFR 677C-->T variant and myocardial infarction, coronary artery occlusion, or both; 80 studies were included. DATA EXTRACTION: Data on genotype frequency and mean homocysteine concentrations by genotype were extracted. Odds ratios were calculated for TT genotype versus CC genotype. Heterogeneity was explored, with stratification by geographical region of the study samples, and meta-regression by difference in mean serum homocysteine concentrations (CC minus TT genotypes) was carried out. RESULTS: 26,000 cases and 31,183 controls were included. An overall random effects odds ratio of 1.14 (95% confidence intervals 1.05 to 1.24) was found for TT versus CC genotype. There was strong evidence of heterogeneity (P < 0.001, I2 = 38.4%), which largely disappeared after stratification by geographical region. Odds ratios in Europe, Australia, and North America attenuated towards the null, unlike those in the Middle East and Asia. CONCLUSIONS: No strong evidence exists to support an association of the MTHFR 677 C-->T polymorphism and coronary heart disease in Europe, North America, or Australia. Geographical variability may be due to higher folate intake in North America and Europe or to publication bias. The conclusion drawn from previous meta-analyses that folic acid, through lowering homocysteine, has a role in prevention of cardiovascular disease is in some doubt.