Results from previous studies suggest that adiponectin levels are associated with risk factors for cardiovascular disease and type 2 diabetes mellitus; however, the genetic and/or environmental components of this relationship have not been characterized. The aims of this study were (1) to assess the presence of pleiotropy between adiponectin levels and risk factors for cardiovascular disease and (2) to study the association of circulating levels of adiponectin with risk factors for cardiovascular disease in the absence and presence of obesity in Mexican American adults from the San Antonio Family Heart Study. Body composition and circulating levels of adiponectin, leptin, and lipid subfractions and measurements of glucose metabolism were measured in 898 subjects. The mean and standard error of the circulating levels of adiponectin was 8.7 ±3.2 μg/ml. Bivariate quantitative analyses between adiponectin levels and phenotypes related to cardiovascular disease and type 2 diabetes mellitus were conducted using the variance decomposition approach implemented in SOLAR. A second analysis in unrelated subjects compared these risk factors between sex and agematched lean and obese subjects with high and low adiponectin levels. We found significant evidence of pleiotropy (i.e., shared genetic effects) between plasma levels of adiponectin and wellestablished risk factors for cardiovascular disease and type 2 diabetes mellitus. Individuals with low adiponectin levels per body weight had more adverse risk profiles. These findings offer new insights into the genetic connection between increasing adiposity and risk for cardiovascular disease and type 2 diabetes mellitus, and they suggest that adiponectin may be an important risk factor for the development of these conditions.