The rs12722 polymorphism in COL5A1 gene has been implicated in the etiology of musculoskeletal soft tissue injuries in several association studies with limited sample size and conflicting results. The purpose of the present systematic review and metaanalysis was to evaluate and synthesize the currently available data on the association between rs12722 and musculoskeletal soft tissue injuries. Five electronic databases including Pubmed, EMBASE, ISI Web of Science, CNKI and Wanfang were searched to identify relevant studies published before 15 May, 2017. Summary odds ratios (ORs) and corresponding 95% confidence intervals (95% CIs) were estimated using the RevMan 5.3 software. Nine studies comprising 1140 cases and 1410 healthy controls met the eligibility criteria. Recessive model was confirmed to be the optimum model (TT vs TC + CC). The results indicated that rs12722 SNP was significantly associated with musculoskeletal soft tissue injuries (OR 1.58, 95% CI 1.33, 1.89; P < 0.00001). When stratified by injury sites, modest but statistically significant association was found in Achilles tendon pathology (ATP), anterior cruciate ligament injuries (ACLI) and tennis elbow (TE). Subgroup-analysis by ethnicity suggested that TT genotype of rs12722 was associated with tendon and ligament injuries in Caucasians (OR 1.59, 95% CI 1.33, 1.90; P < 0.00001) but not in Asians (OR 1.46, 95% CI 0.46, 4.60; P = 0.52). Our findings indicated that rs12722 of COL5A1 was positively associated with tendon and ligament injuries, especially in Caucasian subjects. Individuals with TT genotype were predisposed to higher risk of ATP, ACLI and TE. © Lv et al.