COPD is a multicomponent disease characterized by abnormal inflammatory response of the lungs to noxious particles that is accompanied by systemic effects like weight loss, muscle wasting, reduced functional capacity and impaired health status. A persistent low-grade systemic inflammatory response reflected by enhanced levels of acute phase proteins like C-reactive protein (CRP) and pro-inflammatory cytokines such as tumor necrosis factor (TNF)-alpha, is present in part of the COPD population. The production of inflammatory proteins is partly genetically determined. Several studies have shown that polymorphisms within genes coding for these inflammatory mediators may modulate systemic inflammatory responses. Among all of these genes, the TNF family (TNF-alpha, lymphotoxin (LT)-alph and their receptors TNF-R55 and TNF-R75), interleukin (IL)-6 and CRP gene polymorphisms are the most prominent candidates. However, large carefully designed studies in well-characterized COPD cohorts are required to unravel the exact role of genetic background in the systemic component of this disease.