The causes of idiopathic carpal tunnel syndrome (CTS) remain unknown and the involvement of the tendons within the carpal tunnel structure in the aetiology of CTS cannot be excluded. Variants within the COL5A1 gene, an important regulator of fibril assembly in tendons, have previously been associated with modulating the risk of CTS. Furthermore, proteoglycans are also important structural components of tendons and variants within the aggrecan gene are associated with musculoskeletal soft tissue injuries. The aim of this study was to determine whether ACAN and BGN variants are associated with CTS.Self-reported Coloured participants (n=99), with a history of CTS release surgery (CTS), and 136 control participants, with no history of CTS symptoms (CON), were genotyped for ACAN rs1516797(G/T) and BGN rs1126499(C/T) variants.The BGN CC genotype was significantly over-represented (p=0.0498; OR=0.545, 95% CI=0.30–0.99) in the CON group (71.8%) versus the CTS (58.1%) group. When the previously reported associated COL5A1 genotypes were included in the analysis, COL5A1 and BGN gene–gene interactions were also shown to significantly modulate the risk of CTS in females. In conclusion this is the first study to report that variants within the BGN gene, independently and by interacting with COL5A1 variants, are associated with CTS. Further studies are required to replicate these findings.