The relative efficacy, safety and ecological implications of macrolides vs. quinolones in the treatment of community-acquired pneumonia (CAP) are debatable. We performed a systematic review and meta-analysis of randomized controlled trials comparing any macrolide vs. any quinolone for the treatment of CAP among adult inpatients or outpatients, as monotherapy or both in combination with a beta-lactam. We did not limit inclusion by pneumonia severity, publication status, language or date of publication. The primary outcomes assessed were 30-day all-cause mortality and treatment failure. Two authors independently extracted the data. Fixed effect meta-analysis of risk ratios (RRs) with 95% confidence intervals was performed. Sixteen trials (4989 patients) fulfilling inclusion criteria were identified, mostly assessing outpatients with mild to moderate CAP. All-cause mortality was not significantly different for macrolides vs. quinolones, RR 1.03 (0.63–1.68, seven trials), with a low event rate (2%). Treatment failure was significantly lower with quinolones, RR 0.78 (0.67–0.91, 16 trials). The definition of failure used in the primary studies was not clearly representative of patients’ benefit. Microbiological failure was lower with quinolones, RR 0.63 (0.49–0.81, 13 trials). All adverse events, adverse events requiring discontinuation and any premature antibiotic discontinuation were significantly more frequent with macrolides, mainly on account of gastrointestinal adverse events. Resistance development was not assessed in the trials. Randomized controlled trials show an advantage of quinolones in the treatment of CAP with regard to clinical cure without need for antibiotic modification at end of treatment and gastrointestinal adverse events. The clinical significance of this advantage is unclear.