Several reports suggest that folate has a procarcinogenic effect. Folate has a unique role because its coenzymes are needed for de novo purine and thymine nucleotide biosynthesis. Antifolates, such as methotrexate, are used in cancer treatment. Using a meta-analysis weighted for the duration of folic acid (pteroylglutamic acid) supplementation, we analyzed the cancer incidence of six previously published large prospective folic acid-supplementation trials in men and women. These articles were carefully selected from over 1100 identified using PubMed search. Our analyses suggest that cancer incidences were higher in the folic acid-supplemented groups than the non-folic acid-supplemented groups (relative risk = 1.21 [95% confidence interval: 1.05-1.39]). Folic acid-supplementation trials should be performed with careful monitoring of cancer incidence. Solid monitoring systems to detect side effects, including increase in cancer risk, should be established before the initiation of folic acid supplementation trials. © 2011 Elsevier Ltd.