Interleukin-10 (IL-10) is a centrally operating anti-inflammatory cytokine that plays a crucial role in the regulation of the innate immune system. It has strong inactivating properties on the inflammatory host response and has been related with viral persistence. We aimed to evaluate the association among circulating IL-10, obesity phenotypes, IL-10 and IL-10R1 gene polymorphisms, and the environmental exposure to viral infection. IL-10 -819C/T gene promoter and IL-10 receptor-1 -243A/G gene polymorphisms were studied in 760 subjects, whereas the former was also investigated in a replication study of 676 subjects. The association of circulating IL-10 levels (enzyme-linked immunosorbent assay) with the serum IgG against adenoviruses and enteroviruses was evaluated in a subset of 189 subjects. Circulating levels of IL-10 were increased in obese people and were positively associated with weight, BMI, waist, waist-to-hip ratio, fat mass, systolic pressure, and, interestingly, the titer of adenoviruses and enteroviruses. Obese subjects with adenovirus titer over the median had the highest circulating IL-10 concentration. Both obesity and adenovirus titer were independently associated with IL-10 variance. Nonmorbid obese T carriers for the -819CT IL-10 gene polymorphism had significantly higher BMI and waist circumference, and those with normal fasting glucose had increased fasting triglycerides. G carriers for the -536AG IL-10R1 gene polymorphism had higher systolic and diastolic pressures, and IL-10 levels; and obese G carriers had an increased waist-to-hip ratio. In summary, circulating IL-10 levels were associated not only with obesity status but also with genetic factors and with the exposure to environmental pathogens.