Importance: Body weight fluctuation is associated with greater risks of adverse health outcomes. The effects of intensive weight loss interventions on the association of variability in adiposity measures with adverse health outcomes in individuals with type 2 diabetes (T2D) has not been studied previously. Objective: To evaluate the associations of long-term variability in adiposity indices with cardiovascular disease (CVD) outcomes, and whether these associations are modified by an intensive lifestyle intervention among adults with T2D. Design and Setting: Prospective cohort analysis including participants in the look AHEAD (Action for Health in Diabetes) trial, which included 16 centers in the US. Data analysis was performed from December 2020 to June 2021. Participants: Participants without CVD at baseline (August 2001 – April 2004). Exposure: Variability of body mass index (BMI) and waist circumference (WC) across four annual visits, assessed using the coefficient of variation (CV), variability independent of the mean (VIM), and standard deviation (SD). Main outcomes and measures: (1) all-cause mortality, (2) cardiovascular deaths (deaths from myocardial infarction [MI] or stroke), (3) CVD events (MI, stroke, and/or death from cardiovascular causes). Results: Among 3,604 study participants (mean age 58.4 [SD: 6.6] years, 62.3% women, 66% white), there were 216 CVD events, 33 CVD-deaths, and 166 deaths over a median of 6.7 years. In the control group, the HRs for the highest (Q4) compared to lowest (Q1) quartile of CV of BMI were 4.06 (95%CI 2.17-7.57), 15.28 (95%CI 2.89-80.90), and 2.16 (95%CI 1.21-3.87) for all-cause mortality, CVD mortality, and cardiovascular events, respectively. In the intervention group, the corresponding HRs were 0.99 (95%CI 0.45-2.16), 1.14 (95%CI 0.12-10.53), and 0.77 (95%CI 0.40-1.49). Regarding WC, in the control group, HRs for Q4 were 1.84 (95%CI 1.01-3.35), 6.46 (95%CI 1.16-36.01), and 1.28 (95%CI 0.72-2.29). In the intervention group, HRs were 1.23 (95%CI 0.61-2.46), 0.55 (95%CI 0.15-2.11), and 0.70 (95%CI 0.39-1.25). Conclusions and relevance: In this cohort study of T2D individuals, higher variability of adiposity indices was associated with significantly increased risk of CVD outcomes and death in the control arm, but not in the intensive lifestyle intervention arm.