Smoking is by far the most important cause of COPD and increases its incidence, rate of progression, severity, and morality rate. Tobacco smoke activates macrophages to release chemotactic factors that recruit inflammatory cells from the circulation. All smokers have inflammatory changes in their airways and lungs, particularly in the small airways, but in people with COPD the response to the particulate matter and toxins in tobacco smoke seems to be exaggerated.

Tobacco smoke also results in excessive activity of serine proteases which results in destruction of alveoli. Tissues throughout the body are constantly being remodeled and repaired. As part of this process, structural proteins are broken down and replaced by newly synthesized proteins. The activity of the proteases is regulated by molecules called "anti-proteases" which down-regulated the proteases. One of the important down-regulators is alpha-1 antitrypsin; alpha-1 antitrypsin decreases the activity of proteases, such as elastase, which breaks down the protein elastin. The inflammatory response to tobacco smoke upsets this balance and accelerates protein breakdown in two ways - it both promotes the release proteases, and it inactivates several anti-proteases, such as alpha-1 antitrypsin. Ultimately, this leads to damage to tissue destruction in the walls of the alveoli.

While smoking is the primary risk factor for COPD, the risk is very much influenced by genetic variants effecting alpha-1-antitrypsin activity. There are several alleles that effect the expression of alpha-1 antitrypsin. Most humans (90%) are homozygous and have the "MM" genotype which confers normal activity of alpha-1 antitrypsin. However, other alleles confer less activity as shown in the table below on the left. The risk of COPD is only slightly increased with the MZ and SS genotypes, but risk is somewhat increased with the SZ genotype and very much increased in ZZ individuals. The graph below on the right shows survival curves for ZZ smokers and ZZ non-smokers compared to all males and females in Sweden.