Peroxisome proliferator-activated receptor δ (PPARδ) regulates the expression of genes involved in lipid and carbohydrate metabolism. To examine the association of the functional +294T/C polymorphism of PPARD with human physical performance, the distribution of PPARD alleles and genotypes was studied in a cohort of athletes (N = 1256), stratified by specialization and skill level, and in controls (N = 610). The frequency of PPARD allele C (with a higher transcriptional activity compared to allele T) in the group of endurance-oriented athletes (N = 898) was significantly higher than in controls (18.3% vs. 12.1%, P < 0.0001). Moreover, in the group of endurance-oriented athletes participating in cyclic sports, the frequency of allele C increased with growing skill level. Thus, PPARD allele C was associated with predisposition to endurance performance.