Cigarette smoke has a major impact on health issues worldwide. Although genetics certainly is a factor in the sensitivity to cigarette smoke, other lung environmental factors, such as infection, potentially could interact with cigarette smoke to induce inflammatory changes associated with various diseases. Four groups of BALB/c mice (smoking only; smoking + M. pneumoniae infection; mycoplasma only; saline control) were studied for eight weeks to determine the interactive outcomes of inflammation and structural changes in the smoking plus mycoplasma group. This group did have significantly higher amounts of neutrophil degranulation in the outer airway wall area (smooth muscle to alveolar attachments) (p = 0.03) and mRNA expression of matrix metalloproteinase-9 (p= 0.045). Although there was not a significant difference in alveolar tissue elastin between the groups, the smoking plus mycoplasma group had a level approximately 20% below the other groups. Even in this relatively short duration study, it appears that an infectious process can interact with cigarette smoke to produce a destructive type of inflammatory response (activated neutrophils and metalloproteinase-9) seen in the outer airway wall area.