Background: Evidence has established obesity as a risk factor for total knee replacement (TKR) due to osteoarthritis. Obesity is a risk factor for TKR. Randomized trials such as Look AHEAD (Action for Health in Diabetes) have shown long-term successful weight loss with an intensive lifestyle intervention (ILI). It is unknown, however, if intentional weight loss can reduce the risk of TKR. Methods: Look AHEAD randomized persons aged 45-76 with type 2 diabetes who had overweight or obesity to either an ILI to achieve/maintain 7% weight loss or to standard diabetes support and education (DSE). Reported knee pain was assessed using the Visual Analog Scale and Western Ontario McMaster University Osteoarthritis Index questionnaire in 5125 participants without previous TKR. Cox proportional hazard regression was used to model differences in risk of TKR in relation to randomization group assignment (ILI vs DSE) along with baseline body mass index category and baseline knee pain as potential confounders from baseline through Look AHEAD-Extension. Results: Baseline mean ± SD Western Ontario McMaster University Osteoarthritis Index knee pain scores did not differ by treatment assignment (ILI: 3.6 ± 2.9, DSE: 3.9 ± 3.0, P = .08); as expected due to randomization. During follow up, the 631 (12%) participants who reported having a TKR were more likely to have been heavier (P < .001) and older (P < .001) at enrollment, but risk of TKR did not differ by treatment group assignment (hazard ratio [HR] 1.07, 95% confidence interval [CI] 0.91-1.25, P = .43). Heterogeneity of treatment effect was observed according to baseline knee pain (interaction P = .02). In persons without knee pain at baseline, there was a 29% reduced risk of TKR in ILI compared to DSE (HR 0.71, 95% CI 0.52-0.96). However, in persons with knee pain at baseline, there was no statistically significant association of treatment assignment with respect to subsequent TKR incidence (HR 1.11, 95% CI 0.92-1.33). Conclusion: Findings suggest that intensive lifestyle change including physical activity, dietary restriction and behavioral changes to achieve weight loss for prevention of TKR may be most effective in preventing TKR prior to the development of knee pain.