The aims of this study were to explore whether DNA methylation at INSR and IGF2 mediated the association of prenatal exposure to the Chinese great famine with adulthood waist circumference (WC) and BMI. A total of 235 subjects were selected into the present study from severely affected province and a neighbor province with less severely affected famine in China through multi-stage clustered random sampling. DNA methylation at the INSR and IGF2 gene promoter regions was detected by the Sequenom's MassARRAY system. The "mediation" package of R was used to evaluate the mediation effect of DNA methylation on the association between prenatal exposure to the famine and adult WC and BMI. The results showed that prenatal famine exposure was significantly associated with higher overall methylation level of the INSR gene (d = 3.6%; 95% CI 1.2-6.0; P = 0.027) and larger adulthood WC (d = 2.72 cm; 95% CI 0.20-5.24; P = 0.034). Furthermore, famine significantly increased methylation levels at four CpG sites. Methylation of the CpG7 site mediated 32.0% (95% CI 5.0-100.0%, P = 0.029) of the association between prenatal exposure to the Chinese great famine and adulthood WC. In conclusion, Epigenetic changes to the INSR might mediate the adverse effect of prenatal famine exposure on WC in adulthood.