A series of studies have explored the role of cytosolic serine hydroxymethyltransferase (SHMT1) C1420Tpolymorphism in cancer risk, but their results were conflicting rather than conclusive. To derive a moreprecise estimation of the association between C1420T and cancer risk, the present meta-analysis of 28 availablestudies with 15,121 cases and 18,023 controls was conducted. The results revealed that there was no significantassociation between the polymorphism and cancer risk overall. In stratified analysis by cancer type (breast cancer,gastrointestinal cancer, leukemia, lymphoma, and others), the results showed that 1420T allele was associatedwith decreased risk in leukemia (CT vs. CC: OR= 0.825, 95% CI =0.704-0.966; and CT+TT vs. CC: OR= 0.838,95% CI = 0.722-0.973), but the same results were not present for other cancer types. When subgroup analysiswas performed by source of control (population-based [PB] and hospital-based [HB]), a borderline inverseassociation was observed for the HB subgroup (CT vs. CC: OR= 0.917, 95% CI = 0.857-0.982) but not for thePB subgroup. Stratifying by geographic area (America, Asia and Europe), significant inverse association wasonly found in Asia subgroup (CT vs. CC: OR= 0.674, 95% CI = 0.522-0.870). In summary, the findings suggestthat SHMT1 C1420T polymorphism is not associated with overall cancer development, but might decreasecancer susceptibility of Asians as well as reduce leukemia risk. Large well-designed epidemiological studies willbe necessary to validate the risk identified in the current meta-analysis.