Chronic Rhinosinusitis with Nasal Polyps (CRSWNP) is a complex and persistent inflammatory disease of the paranasal sinus mucosa. It is clinically characterized by long-standing sinonasal mucosal inflammation, severe nasal congestion, continuous anterior and posterior rhinorrhea, facial pressure or fullness, and partial or complete loss of olfactory function. Functional Endoscopic Sinus Surgery (FESS) remains the primary surgical procedure of choice for CRSWNP cases that are refractory to conventional medical management. The ultimate goal of FESS is to restore surgical drainage pathways, improve sinus clearance, and re-establish proper sinus ventilation. This surgical intervention creates an anatomical environment optimal for post-operative topical medical therapies. Nevertheless, persistent mucosal inflammation, recalcitrant tissue edema, and post-operative recurrence of polypoid tissue represent major challenges during long-term follow-up. Despite initial surgical success, recurrent nasal polyposis remains a significant clinical challenge following Functional Endoscopic Sinus Surgery (FESS). In cases of recurrence, medical management plays a pivotal role in controlling mucosal inflammation and delaying or preventing re-operation. Diverse pharmacological interventions have been explored to control post-operative recurrence, including standard anti-inflammatory regimens as well as alternative systemic therapies such as some antibiotics, long-term macrolides, and novel biologics targeting specific inflammatory pathways. Macrolides, particularly 15-membered azalides such as Azithromycin, possess significant immunomodulatory and anti-inflammatory properties distinct from their classic antibacterial actions. When administered in low doses over extended periods, Azithromycin actively downregulates pro-inflammatory cytokines, inhibits tissue neutrophil infiltration, decreases goblet cell hypersecretion, and fosters mucosal healing and epithelial restoration.