The role of macrolides for the prevention and treatment of feeding intolerance (FI) in preterm low birth weight (LBW) infants has not been well established. To assess the efficacy and safety of macrolides to prevent or treat FI in preterm LBW infants. A systematic review and meta-analysis (PROSPERO ID: CRD42020170519) was conducted for English articles published since inception to March 2020, using MEDLINE, EMBASE, and the Cochrane Controlled Trials Register. Search terms included preterm low birth weight infants, macrolides, erythromycin, azithromycin, clarithromycin, and feeding intolerance. Randomized controlled trials (RCTs) assessing the effects of macrolide therapy on the time to achieve full enteral feeding (FEF;150 mL/kg/day), duration of parenteral nutrition (PN), hospitalization, and adverse events in preterm LBW infants were included. Independent extraction of data was done by both authors using predefined data-sheet. Very-low to low-quality evidence from 21 RCTs, 19 for erythromycin (prophylaxis-6, rescue-13) and 2 for clarithromycin (prophylaxis-1, rescue-1) demonstrated a significantly beneficial role of erythromycin for an earlier FEF, both as a prophylaxis (SMD-0.53, 95% CI – 0.74,- 0.33; 6 studies, n = 368) as well as rescue (SMD-1.16, 95% CI – 1.88, – 0.44; 11 studies, n = 664). Rescue therapy was also beneficial for a significant reduction in the duration of PN, hospitalization, incidences of sepsis, necrotizing enterocolitis, and cholestasis. No arrhythmia or infantile hypertrophic pyloric stenosis was reported.Conclusions: Erythromycin therapy, both as prophylaxis and rescue, is beneficial to reduce the time to achieve FEF in preterm LBW infants, at no higher risk of adverse events.