Thymidylate synthase and serine hydroxymethyltransferase are involved in folate metabolism. In a case-control study, including 768 cases and 709 controls, we investigated the associations between colorectal adenomas and TS tandem repeat and SHMT1 C1420T polymorphisms, and the interplay with B-vitamins. The polymorphisms were not associated with adenomas, but there was a borderline significant interaction between TS genotype and vitamin B6: the association between vitamin B6 and adenomas seemed positive in TS 3R/3R individuals, but inverse in TS 2R/2R individuals. This study does not provide evidence for a role of SHMT1 genotype in adenoma occurrence. Future research has to indicate whether the TS-B6 interplay is a real effect or a chance finding.