The purpose of this study was to investigate individually and in combination the association between the ACE (I/D), NOS3 (Glu298Asp), BDKRB2 (-9/+9), UCP2 (Ala55Val) and AMPD1 (Gln45Ter) variants with endurance performance in a large, performance-homogenous cohort of elite Polish half marathoners. The study group consisted of 180 elite half marathoners: 76 with time < 100 minutes and 104 with time > 100 minutes. DNA of the subjects was extracted from buccal cells donated by the runners and genotyping was carried out using an allelic discrimination assay with a C1000 Touch Thermal Cycler (Bio-Rad, Germany) instrument with TaqMan® probes (NOS3, UCP2, and AMPD1) and a T100™ Thermal Cycler (Bio-Rad, Germany) instrument (ACE and BDKRB2). We found that the UCP2 Ala55Val polymorphism was associated with running performance, with the subjects carrying the Val allele being overrepresented in the group of most successful runners (<100 min) compared to the >100 min group (84.2 vs. 55.8%; OR = 4.23, p < 0.0001). Next, to assess the combined impact of 4 gene polymorphisms, all athletes were classified according to the number of 'endurance' alleles (ACE I, NOS3 Glu, BDKRB2 -9, UCP2 Val) they possessed. The proportion of subjects with a high (4-7) number of 'endurance' alleles was greater in the better half marathoners group compared with the >100 min group (73.7 vs. 51.9%; OR = 2.6, p = 0.0034). These data suggest that the likelihood of becoming an elite half marathoner partly depends on the carriage of a high number of endurance-related alleles.