Background. Although variants within genes that encode protein components of several biological systems have been associated with athletic performance, limited studies have investigated the collagen genes that encode the structural components of connective tissues.Objective. To investigate the association of variants within collagen genes with endurance performance in South African (SA) Ironman triathletes.Methods. A total of 661 white, male participants were recruited from four SA Ironman triathlon events for this genetic case-control association study. All participants were genotyped for COL3A1 rs1800255 (G/A) and COL12A1 rs970547 (A/G).Results. No independent associations were identified between COL3A1 rs1800255 and COL12A1 rs970547 and overall finishing time or time to complete any of the individual components (3.8 km swim, 180 km bike or 42.2 km run) of the 226 km event. The major G+A-inferred pseudo-haplotype, constructed from COL3A1 rs1800255 and COL12A1 rs970547, was, however, significantly (p=0.010 and p=0.027) overrepresented in the fast run tertile (58.7%) compared with the middle (53.5%) and slow (49.5%) run tertiles, respectively. The major G+T+A-inferred pseudo-haplotype, constructed from COL3A1 rs1800255, COL5A1 rs12722 (T/C) and COL12A1 rs970547, was again significantly (p=0.022) over-represented in the fast run tertile (35.2%) compared with the slow run tertile (28.9%).Conclusion. Our main novel finding was that the COL3A1 rs1800255 and COL12A1 rs970547 variants interacted to modulate endurance running performance in the four SA Ironman triathlons investigated. In addition, the interaction between these variants and COL5A1 rs12722 appeared to modulate endurance running performance.