Context: The H-allele of the R298H polymorphism in the prostaglandin E synthase 2 (PTGES2) gene was associated with lower risk of diabetes type 2. Aim: To explore the association between the PTGES2 R298H SNP and body mass index (BMI). Methods: We analyzed the R298H SNP (rs13283456) and three haplotype single-nucleotide polymorphisms (rs884115, rs10987883, and rs4837240) covering a 20 kb gene region in population-based surveys of the Kooperative Gesundheitsforschung in der Region Augsburg study cohort with 8079 participants. Results: A statistically significant difference in BMI between the heterozygous PTGES2 R298H genotype and the homozygous R/R genotype was found in males but not in females. Males with the R/H genotype showed a decrease in BMI of-0.30 BMI units (95% CI:-0.55,-0.04, p = 0.02) in comparison to R/R males. A haplotype comprising the minor allele of PTGES2 R298H showed a significant decrease of-0.23 BMI units in males (-0.45,-0.02; p = 0.04) but not in females. Other haplotypes and haplotype single-nucleotide polymorphisms were not significantly associated with BMI. Conclusion: We found a marginal but significant influence of the PTGES2 298H SNP on BMI in a large population-based study.