Anterior cruciate ligament (ACL) rupture is one the most common musculoskeletal soft tissue injuries of the knee. Although the exact mechanisms of this injury remain uncertain, genetic variants have been considered to be an intrinsic risk factor associated with ACL rupture. Therefore, the aim of the present study was to determine whether the adiponectin +276G/T polymorphism is associated with susceptibility to ACL rupture in a Thai population. Genotyping for rs1501299 was conducted in 98 participants with ACL rupture and 95 healthy controls by polymerase chain reaction-restriction fragment length polymorphism analysis. The results demonstrated that the GG genotype and G allele were significantly associated with an increased risk of ACL rupture [odds ratio (OR)=1.91, P=0.026; OR=1.89, P=0.004], whereas the TT genotype was significantly associated with a reduced risk of ACL rupture (OR=0.32, P=0.019). Furthermore, ACL injury patients with non-contact sports carrying the GG genotype and G allele exhibited a significantly higher risk of ACL rupture (OR=2.13, P=0.031; OR=1.84, P=0.029). In addition, overweight patients carrying the GG genotype and G allele had a significantly increased (8-fold) risk of ACL rupture (OR=8.00, P<0.001; OR=5.15, P<0.001), whereas overweight patients with the adiponectin +276G/T GT genotype had a significantly lower risk of ACL rupture (OR=0.13, P<0.001). Therefore, the adiponectin +276G/T polymorphism GG genotype and G allele were significantly associated with the risk of ACL rupture, particularly in overweight patients. These findings indicate that the adiponectin +276G/T polymorphism may play a role in the development of ACL rupture in the Thai population.