Obesity is a well-recognized risk factor for osteoarthritis (OA). We aim to investigate if obesity is the causal antecedent of early joint replacement in patients with OA and characterize the body mass index (BMI)-associated pathological changes in the osteochondral unit. We analyzed the impact of BMI on the age at which patients underwent total knee replacement (TKR). A total of 41,023 cases of TKR from the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) were assessed. It revealed that approximately 57% of TKR applied for patients with primary OA were obese. There was a significant progressive reduction in the age at which patients with increased BMI. The mean age of TKR in obese class III patients was 8 years younger than normal-weight patients. We then investigated the effect of BMI on pathological changes of knee joints in a representative cohort undergoing TKR. Histopathological examination revealed, for the first time, that horizontal fissuring at the osteochondral interface (Figure 1) was the major pathological feature of obesity-related OA. The frequency of horizontal fissure was strongly associated with increased BMI in the predominant compartment. An increase in one unit of BMI (1 kg/m2) increased the odds of horizontal fissures by 14.7%. Over 80% of the horizontal fissures were attributable to obesity. Reduced cartilage degradation and alteration of subchondral bone microstructure were also associated with increased BMI. In conclusion, obesity is strongly associated with a younger age of TKR. Due to differences in the mechanical properties of cartilage, calcified cartilage and subchondral bone, secondary shear stress generated by high body weight in obesity-related OA induces horizontal fissures at the osteochondral interface. This key pathological feature may be the cause of earlier TKR in patients with obesity. This finding will draw a considerable attention to the osteochondral interface as a therapeutic target for obesity-related OA.