The authors hypothesized that variants within genes, such as COL5A1, COL3A1, COL6A1, and COL12A1, that code for connective tissue components of the musculoskeletal system may modulate susceptibility to exercise-associated muscle cramping (EAMC). Specifically, the aim of this study was to investigate if the COL5A1 rs12722 (C/T), COL3A1 rs1800255 (G/A), COL6A1 rs35796750 (T/C), and COL12A1 rs970547 (A/G) polymorphisms are associated with a history of EAMC.Retrospective genetic case-control association study.Participants were recruited at triathlon and ultra-marathon events and were asked to report physical activity, medical history, and cramping history.One hundred sixteen participants with self-reported history of EAMC within the past 12 months before an ultra-endurance event were included as cases in this study (EAMC group). One hundred fifty participants with no self-reported history of previous (lifelong) EAMC were included as controls (NON group).All participants were genotyped for the selected variants.Differences in genotype frequency distributions, for COL5A1 rs12722, COL3A1 rs1800255, COL6A1 rs35796750, and COL12A1 rs970547, among the cases and controls.The COL5A1 CC genotype was significantly overrepresented (P = 0.031) among the NON group (21.8%) when compared with the EAMC group (11.1%). No significant genotype differences were found for the COL3A1 (P = 0.828), COL6A1 (P = 0.300), or COL12A1 (P = 0.120) genotypes between the EAMC and NON groups.This study identified, for the first time, the COL5A1 gene as a potential marker for a history of EAMC.