Background Obesity is associated with increased mortality and weight loss trials show rapid improvement in many mortality risk factors. risks (RR) and 95% confidence Isorhamnetin 3-O-beta-D-Glucoside intervals (95% CI) were estimated for each trial. For trials reporting at least one death (n = 12) a summary estimate was calculated using the Mantel-Haenszel method. Sensitivity analysis using sparse data methods included remaining trials. Results Trials enrolled 17 186 participants (53% female mean age at randomization = 52 years). Mean body mass indices ranged from 30-46 kg/m2 follow-up times ranged from 18 months to 12.6 years (mean: 27 months) and average weight loss in reported trials was 5.5±4.0 kg. A total of 264 deaths were reported in weight Isorhamnetin 3-O-beta-D-Glucoside loss groups and 310 in non-weight loss groups. The weight loss groups experienced a 15% lower all-cause mortality risk (RR = 0.85; 95% CI: 0.73-1.00). There was no evidence for heterogeneity of effect (Cochran’s Q = 5.59 (11 d.f.; p = 0.90); I2 = 0). Results were similar in trials with a mean age at randomization ≥55 years (RR = 0.84; 95% CI 0.71-0.99) and a follow-up time of ≥4 years (RR = 0.85; 95% CI 0.72-1.00). Conclusions In obese adults intentional weight loss may be associated with approximately a 15% reduction in all-cause mortality. Introduction Advanced age and obesity are risk factors for disability morbidity and mortality [1-3]. Weight loss interventions in overweight and obese older adults positively affect several strong risk factors for mortality including: circulating IL-6 levels [4-6] blood pressure [7 8 fasting plasma glucose [9 10 gait speed [11-13] and cardiorespiratory fitness [12 14 15 Yet many observational studies in middle-aged and older adults report an association between weight loss and increased mortality [16-18]. Difficulty reconciling these contradictory findings (the Isorhamnetin 3-O-beta-D-Glucoside so-called “obesity paradox”) coupled with the strong negative prognostic implication of rapid involuntary weight loss with advanced age has led to a reluctance to recommend weight loss in older adults [19]. Attempts to refine observational analyses to avoid confounding (i.e. distinguishing between intentional and unintentional weight loss and restricting populations to those without co-morbid conditions or non-smokers) typically reveal no increase and perhaps some decrease in mortality risk with intentional weight loss [20 21 Indeed results from the Swedish Obesity Study show a 24% reduction in all-cause 10-year mortality associated with gastric banding compared to matched-obese controls [22]. However as a non-randomized study it is unclear if selection bias or confounding contributed to the observed mortality advantage. Isorhamnetin 3-O-beta-D-Glucoside Although Isorhamnetin 3-O-beta-D-Glucoside results from a randomized controlled trial (RCT) of weight loss would theoretically resolve these issues such a trial would require a large sample size over a long duration to detect clinically meaningful differences in mortality. In light of the high prevalence of obesity its negative impact on health and quality of life and the discrepancy between the proven risk factor improvements of short-term intentional weight loss and the inverse association of weight loss with increased all-cause mortality frequently seen in observational Arnt studies we conducted a meta-analysis to estimate the effect of interventions which included intentional weight loss on all-cause mortality in overweight and obese adults. We hypothesized that intentional weight loss would be associated with reduced all-cause mortality. Further as weight loss in older persons is a cause of clinical concern that may lead health care providers to recommend against weight loss for obese older adults we sought to examine the effects in a subset of trials with a mean baseline age of at least 55 years. Materials and Methods Study selection and data extraction We sought to identify all published RCTs of intentional weight loss that reported mortality data either as an endpoint or as an adverse event including study designs where participants were randomized to weight loss or non-weight loss or weight loss plus a co-intervention (e.g. weight loss plus exercise) or the weight.