We reported defective efferocytosis associated with cigarette smoking and/or airway inflammation in chronic lung diseases including COPD, severe asthma and childhood bronchiectasis. We also showed defects in phagocytosis of non-typeable H. influenzae (NTHi), a common colonizer of the lower airway in these diseases. These defects could be substantially overcome with low-dose Azithromycin; however, chronic usage may induce bacterial resistance. We investigated two novel macrolides, GS-459755 (2'-desoxy-9-(S)-erythromycylamine) and GS-560660 (Azithromycin-based 2'-desoxy molecule) with significantly diminished antibiotic activity against S. aureus, S. pneumonia, M. catarrhalis, and H. influenzae. We tested their effects on efferocytosis, phagocytosis of NTHi, cell viability, receptors involved in recognition of apoptotic cells and/or NTHi (flow cytometry), secreted and cleaved intracellular IL-1β (CBA, immunofluorescence/ confocal microscopy) and NLRP3, using primary alveolar macrophages and THP-1 macrophages ± 10% cigarette smoke extract. Dose response experiments showed optimal pro-phagocytic effects of GS-459755 and GS-560660 at concentrations of 0.5-1µg/mL, comparable to our findings with Azithromycin. Both macrolides significantly improved phagocytosis of apoptotic cells and NTHi (eg, increases in efferocytosis and phagocytosis of NTHi: GS-459755 23% and 22.5% p=0.043; GS-560660 23.5% and 22% p=0.043, respectively). Macrophage viability remained >85% following 24h exposure to either macrolide at concentrations up to 20µg/mL. Secreted and intracellular cleaved IL-1β were decreased with both macrolides with no significant changes in recognition molecules MerTk, SRA1, TLR2/4 or CD36. Particulate cytoplasmic immunofluorescence of NLRP3 inflammasome was also significantly reduced. We conclude that GS-459755 and GS-560660 may be useful for reducing airway inflammation in chronic lung diseases without inducing bacterial resistance.