Various chronic inflammatory airway diseases can be treated with low-dose, long-term (LDLT) macrolide therapy. LDLT macrolides can be one of the therapeutic options for chronic rhinosinusitis (CRS) due to their immunomodulatory and anti-inflammatory actions. Currently, various immunomodulatory mechanisms of the LDLT macrolide treatment have been reported, as well as their antimicrobial properties. Several mechanisms have already been identified in CRS, including reduced cytokines such as interleukin (IL)-8, IL-6, IL-1β, tumor necrosis factor-α, transforming growth factor-β, inhibition of neutrophil recruitment, decreased mucus secretion, and increased mucociliary transport. Although some evidence of effectiveness for CRS has been published, the efficacy of this therapy has been inconsistent across clinical studies. LDLT macrolides are generally believed to act on the non-type 2 inflammatory endotype of CRS. However, the effectiveness of LDLT macrolide treatment in CRS is still controversial. Here, we reviewed the immunological mechanisms related to CRS in LDLT macrolide therapy and the treatment effects according to the clinical situation of CRS.