Rationale: Proline-glycine-proline (PGP), a neutrophil chemoattractant derived from the enzymatic breakdown of collagen, is elevated in sputum of patients with chronic obstructive pulmonary disease (COPD) and may contribute to disease progression. Whether sputum levels of PGP respond to therapy for COPD or predict outcomes is unknown. Objectives: We conducted a study ancillary to a multicenter trial of the efficacy of azithromycin treatment for 1 year in preventing COPD exacerbations to test whether sputum levels of PGP were altered by treatment or associated with exacerbation frequency. Methods: We collected remnant sputa from trial participants and assayed them in a blinded fashion for PGP, myeloperoxidase and matrix metalloproteinase (MMP)-9 and for the ability to generate PGP from collagen ex vivo. Once the parent trial was unblinded, the results were correlated with use of azithromycin or placebo and exacerbations in participants. Results: Azithromycin treatment significantly reduced sputum levels of PGP and myeloperoxidase in patients with COPD, particularly with increased duration of therapy. We found no difference in sputum MMP-9 or PGP generation between participants taking azithromycin or placebo. Sputum PGP levels were highest around the time of an exacerbation and declined with successful treatment. Conclusions: These data support a role for PGP in the airway and parenchymal neutrophilic inflammation that drives COPD progression and exacerbations, and provide new information on the anti-inflammatory properties of macrolides. PGP may have potential as a target for novel anti-inflammatory therapies in COPD and as a biomarker for clinical trials.