OBJECTIVE: Numerous studies have documented an obesity paradox in which the overweight and obese elderly have a better prognosis than those with ideal body weight. Good prognosis among the overweight or obese elderly may reflect the relative safety of storing the harmful lipophilic chemicals, known as persistent organic pollutants (POPs), in adipose tissue rather than in other critical organs. Therefore, we hypothesized lower mortality among the obese elderly with a higher body burden of POPs, but this pattern may not exist among the obese elderly with a lower body burden of POPs. PARTICIPANTS: Using the National Health and Nutrition Examination Survey (NHANES) 1999-2004 study with a mean 4.2-year follow-up, we tested whether the association between fat mass and total mortality in 635 (652 for organochlorine pesticides) elderly participants aged ≥70 years differed depending on serum concentrations of 23 POPs. RESULTS: There were statistically significant interactions between fat mass and POPs in predicting total mortality. In those with low POP concentrations, there was no obesity paradox; mortality increased with fat mass (hazard ratios about 2-3 in the highest vs. lowest quintile of fat mass). However, consistent with an obesity paradox, these patterns completely disappeared in those with high POP concentrations. Compared with the lowest quintile of fat mass, statistically significantly lower mortality was observed in the elderly in the third to fifth quintiles of fat mass. In the case of polychlorinated biphenyls, the mortality in the highest quintile of fat mass was only one-fifth of that in the lowest quintile. CONCLUSION: These findings are consistent with our hypothesis that adipose tissue provides relatively safe storage of toxic lipophilic chemicals, a phenomenon that could explain the obesity paradox. Although weight loss may be beneficial among the obese elderly with low POP concentrations, weight loss in the obese elderly with higher serum concentrations of POPs may carry some risk.