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An adverse fetal environment may permanently modify the effects of specific genes on glucose tolerance, insulin secretion, and insulin sensitivity. In the present study, we assessed a possible interaction of the peroxisome proliferator–activated receptor (PPAR)-γ2 Pro12Ala polymorphism with prenatal exposure to famine on glucose and insulin metabolism.We measured plasma glucose and insulin concentrations after an oral glucose tolerance test and determined the PPAR-γ2 genotype among 675 term singletons born around the time of the 1944–1945 Dutch famine.A significant interaction effect between exposure to famine during midgestation and the PPAR-γ2 Pro12Ala polymorphism was found on the prevalence of impaired glucose tolerance and type 2 diabetes. The Ala allele of the PPAR-γ2 gene was associated with a higher prevalence of impaired glucose tolerance and type 2 diabetes but only in participants who had been prenatally exposed to famine during midgestation. Similar interactions were found for area under the curve for insulin and insulin increment ratio, which were lower for Ala carriers exposed to famine during midgestation.The effects of the PPAR-γ2 Pro12Ala polymorphism on glucose and insulin metabolism may be modified by prenatal exposure to famine during midgestation. This is possibly due to a combined deficit in insulin secretion, as conferred by pancreatic β-cell maldevelopment and carrier type of the Ala allele in the PPAR-γ2 gene.