This study aimed to compare the outcome of patients with severe community-acquired pneumonia (SCAP) treated with the combination of either β-lactam-quinolone (βQ) or β-lactam-macrolide (βM) antibiotics. We retrospectively studied a cohort of patients with SCAP treated from January 2000 to December 2010 at a mixed university-level intensive care unit (ICU). APACHE II score, SCAP severity assessed by IDSA/ATS score, first antibiotic treatment initiated during the initial 24 h of admission, ICU and hospital length of stay (LOS), and ICU, hospital, 30 and 60-day mortalities were assessed. Altogether, 210 patients with SCAP were analyzed, 104 in the βQ arm and 106 in the βM arm. Median APACHE II scores on admission were higher in the βM group (22 vs. 18, P = 0.003). More patients in the βQ group required mechanical ventilation (63.1% vs. 42.5%, P = 0.004) and fulfilled IDSA/ATS SCAP criteria (n = 87; 83.7%) than those in the βM group (n = 73; 68.9%; P = 0.015). Thirty-day mortality was 16.3% in the βQ group and 24.5% in the βM group (P = 0.17), and with septic shock mortality was 19.6% and 32.6%, respectively (P = 0.16). On APACHE II and IDSA/ATS SCAP score adjusted multivariate logistic regression analysis, the βM group had a slightly higher but not significant odds ratio (OR) for a 30-day mortality compared to the βQ group (OR 1.4; 95% CI, 0.62-3.0; P = 0.44). Thirty-day mortality rate of SCAP patients did not differ whether they were treated with either βQ or βM combination.