HIV1(+) smokers develop emphysema at an earlier age and with a higher incidence than HIV1(-) smokers. Since human alveolar macrophages (AMs) are capable of producing proteases that degrade extracellular matrix components, we hypothesized that up-regulation of AM matrix metalloproteinases may be associated with the emphysema of HIV1(+) smokers. Microarray analysis was used to screen which matrix metalloproteinases (MMPs) genes were expressed by AM of HIV1(+) smokers with early emphysema. For each of the MMP genes expressed (MMP-1, -2, -7, -9, -10, -12 and -14), TaqMan PCR was used to quantify the relative expression in AM from four groups of individuals: HIV1(-) healthy nonsmokers, HIV1(-) healthy smokers, HIV1(-) smokers with early emphysema, and HIV1(+) smokers with early emphysema. While AM gene expression of MMPs was higher in HIV1(-) individuals with emphysema in comparison with HIV1(-) healthy smokers, for the majority of the MMPs (-1, -7, -9, and -12), AM expression from HIV1(+) smokers with early emphysema was significantly higher than in HIV1(-) smokers with early emphysema. HIV1(+) individuals with early emphysema also had higher levels of epithelial lining fluid (ELF) MMPs (-2, -7, -9, and -12) than the 3 HIV1(-) groups. ELF MMP (-2,-7,-9, and -12) levels were similar in HIV1(+) nonsmokers compared with HIV1(-) nonsmokers. Interestingly, the active forms of MMP-2, -9, and -12 were exclusively detected in ELF from HIV1(+) individuals with early emphysema. Since the activities of the up-regulated AM MMPs include collagenases, gelatinases, matrilysins, and elastase, these data suggest that up-regulated AM MMP genes and activation of MMP proteins may contribute to the emphysema of HIV1(+) individuals who smoke.