Aims. To evaluate the effect of an intensive lifestyle intervention (ILI) on the underlying structural and functional cardiac substrate of atrial fibrillation (AF) in overweight or obese people with metabolic syndrome (MetS). Methods. Participants of the PREDIMED-PLUS trial (n=6874) were randomised 1:1 to an ILI program based on an energy-reduced Mediterranean Diet, increased physical activity, and cognitive-behavioural weight management, or to a control intervention of low-intensity dietary advice. Transthoracic echocardiography (TTE) was evaluated in a subsample of 534 participants by a core lab at baseline, 3-year and 5-year follow-up. Mixed models were used to evaluate the effect of the ILI on left atrial (LA) structure and function. Results. In the subsample (n=534), mean age at inclusion was 66 years (SD 5 years), and 40% of the participants were women. Over the 5-year period, both groups experienced worsening of LA structure and function, with increases in LA volumes and stiffness index and decreases in LA longitudinal strain, LA function index and LA emptying fraction over time. Changes in the ILI and control group were not significantly different for any of the primary outcomes (LA emptying fraction: -0.95% (95%CI -0.93, -0.98) in control group, -0.97% (95%CI -0.94, -1.00) in ILI group, pbetween groups=0.80; LA longitudinal strain: 0.82% (95%CI 0.79, 0.85) in control group, 0.85% (95%CI 0.82, 0.89) in ILI group, pbetween groups=0.24) or any of the secondary outcomes. Conclusions. In overweight or obese people with MetS, an ILI had no impact on the underlying structural and functional cardiac substrate of AF, as assessed by transthoracic echocardiography.