The prostaglandin E synthase 2 (PTGES2) gene maps to a locus linked to obesity and is involved in the synthesis of the antilipolytic compound prostaglandin E(2). In a recent study, we found an association of the minor PTGES2 Arg298His allele and lower risk of type 2 diabetes mellitus in the European Investigation into Cancer and Nutrition (EPIC) and Cooperative Health Research in the Augsburg Region (KORA) cohorts. Here, we employed our Metabolic Intervention Cohort Kiel (MICK) to assess the influence of the PTGES2 Arg298His polymorphism on a wider scale of parameters of the metabolic syndrome and postprandial metabolism. In comparison to subjects homozygous for the Arg allele, carriers of the His-allele showed significantly lower fasting insulin (geometric mean +/- SEM: 11.8 muU/mL, 11.41-12.25 versus 13.0, 12.71-13.33; p = 0.023), lower postprandial insulin levels after an oral glucose tolerance test (area under the curve 77.2, 74.07-80.52 versus 81.2, 78.8-83.63; p = 0.023) and lower homeostasis model assessment (HOMA)-insulin-resistance (3.030, 2.909-3.157 versus 3.346, 3.257-3.438; p = 0.041) and HOMA-beta-cell-function (107.2, 104.04-110.52 versus 117.2, 114.65-119.71; p = 0.019). Adjustment for body mass index (BMI) resulted in a loss of these significant differences. BMI tended to show lower values in His-allele carriers, (p = 0.067). In conclusion, risk-reducing effects of the minor His allele of the PTGES2 Arg298His polymorphism could be mediated partly by lowered BMI.