Chronic obstructive pulmonary disease (COPD) is associated with a systemic inflammatory state, marked by elevations in serum inflammatory markers including C-reactive protein (CRP). The present study sought to determine epidemiological predictors of CRP levels, to estimate the genetic influence on CRP levels, and to identify genetic variants that affect CRP in a family-based study of COPD. CRP was measured by a high-sensitivity assay in participants from the Boston Early-Onset COPD Study. Predictors of CRP level were determined using multilevel linear models. Variance component analysis was used to estimate heritability and to perform genome-wide linkage analysis for CRP levels. Two variants in the surfactant protein B (SFTPB) gene were tested for association with CRP levels. Increased age, female sex, higher body mass index, greater smoking pack-yrs and reduced forced expiratory volume in one second were all associated with increased CRP levels. There was a significant genetic influence on CRP (heritability = 0.25). Genome-wide linkage analysis revealed several potentially interesting chromosomal regions, though no significant evidence for linkage was found. A short tandem repeat marker near SFTPB was significantly associated with CRP levels. There is a genetic influence on C-reactive protein levels in chronic obstructive pulmonary disease patients. Preliminary evidence suggests an association of the surfactant protein B gene with systemic inflammation in chronic obstructive pulmonary disease.