Cigarette smoking is a primary determinant of chronic obstructive pulmonary disease (COPD), which is the fourth leading cause of morbidity and mortality in the United States. Unique proteins associated with COPD capable of differentiating subjects likely to experience rapid (RPD) or slow (SLW) decline in lung function have been identified using comprehensive high-throughput proteomic approaches. Thirty peptides, which mapped to 21 unique proteins, were linearly associated with annualized rates of lung function decline among smokers with COPD characterized as having rapid or slow decline and smokers without COPD. Using three different statistical approaches to assess the data, the RPD and SLW groups are differentiated by 55 peptides, which mapped to 33 unique proteins. A number of the identified peptides are proteolytic fragments of proteins that are involved in the complement and/or coagulation systems, have anti-protease activity, or metabolic functions.