Whether short sleep duration or high sleep variability may predict less weight loss and reduction in measures of adiposity in response to lifestyle interventions is unknown. The aim of this study was to compare the 12-month changes in weight and adiposity measures between those participants with short or adequate sleep duration and those with low or high sleep variability (intra-subject standard deviation of the sleep duration) in PREvención con DIeta MEDiterránea (PREDIMED)-Plus, a primary prevention trial based on lifestyle intervention programs. Prospective analysis of 1986 community-dwelling subjects (mean age 65 years, 47% females) with overweight/obesity and metabolic syndrome from the PREDIMED-Plus trial was conducted. Accelerometry-derived sleep duration and sleep variability and changes in average weight, body mass index (BMI), and waist circumference (WC) attained after 12-month interventions were analyzed. The adjusted difference in 12-month changes in weight and BMI in participants in the third tertile of sleep variability was 0.5 kg (95% CI 0.1 to 0.9; p = 0.021) and 0.2 kg/m (0.04 to 0.4; p = 0.015), respectively, as compared with participants in the first tertile. The adjusted difference in 12-month changes from baseline in WC was -0.8 cm (-1.5 to -0.01; p = 0.048) in participants sleeping <6 h, compared with those sleeping between 7 and 9 h. Our findings suggest that the less variability in sleep duration or an adequate sleep duration the greater the success of the lifestyle interventions in adiposity.