Background Osteoarthritis (OA) of the knee is a common and disabling condition. We wanted to investigate the modifiable risk factors Body Mass Index (BMI) and physical activity, using knee replacement (KR) as a marker for severely symptomatic disease, focusing on the interaction between these risk factors. Methods 315,495 participants (mean age 43.0 years) from national health screenings were followed prospectively with respect to KR identified by linkage to the Norwegian Arthroplasty Register. Data were analysed by Cox proportional hazard regression. Results During 12 years of follow up 1,323 individuals received KR for primary OA. There was a dose–response relationship between BMI and heavy labour, and later KR. Comparing the highest versus the lowest quarter of BMI, the relative risk was 6.2 (95% CI: 4.2-9.0) in men and 11.1 (95% CI: 7.8-15.6) in women. Men reporting intensive physical activity at work had a relative risk of 2.4 (95% CI: 1.8-3.2) versus men reporting sedentary activity at work, the corresponding figure in women being 2.3 (95% CI: 1.7-3.2). The effect of BMI and physical activity at work was additive. The heaviest men with the most strenuous work had a RR of 11.7 (95% CI: 5.9-23.1) compared to the ones with the lowest BMI and most sedentary work. For women the corresponding RR was 15.8 (95% CI: 8.2-30.3). There was no association between physical activity during leisure and KR. Conclusion We found that a high BMI and intensive physical activity at work both contribute strongly to the risk of having a KR. As the two risk factors seem to act independently, people with strenuous physical work with a high BMI are at particularly high risk for severely disabling OA of the knee, and should be targeted with effective preventive measures.