Purpose: The cost-effectiveness of different guideline-concordant antimicrobial regimens for elderly patients with community-acquired pneumonia (CAP) was rarely discussed. This study attempts to explore the most appropriate cost-effectiveness of guideline-concordant antimicrobial regimen for elderly patients with CAP in general wards. Patients and Methods: This was a multicenter, retrospective, 4:2:1 matched study enrolling 511 elderly patients with CAP hospitalized in general wards. Two hundred ninety-two patients prescribed with beta-lactam monotherapy (group A), 146 patients prescribed with fluoroquinolone monotherapy (group B) and 73 patients prescribed with beta-lactamimacrolide combination therapy (group C). Clinical outcomes and medical costs were analyzed by chi(2) test for categorical variables or Kruskal-Wallis H-test for continuous variables. Results: There were no statistical differences in imaging features, etiology and complications during hospitalization among these three groups. The rates of clinical failure occurrence, in-hospital mortality, 30-day mortality and 60-day mortality also had no significant differences among group A, B and C patients; however, the median length of stay (LOS) in group A patients was 12.0 days, which was significantly higher than that in group B and C patients (both 10.0 days, p<0.02). The median total, drug, and antibiotic costs for one elderly CAP episode in group B patients were RMB 10368.4, RMB 3874.8, and RMB 1796.3, respectively, which were significantly lower than those in group A and C patients (p<0.01). Conclusion: Non-inferiority of clinical failure occurrence and short-term mortality was observed in different guideline-concordant antimicrobial regimens for elderly patients with CAP in general wards; however, the median LOS and hospitalization-associated costs for one elderly CAP episode with fluoroquinolone monotherapy were significantly lowest, and this strategy was considered to be the most cost-effective strategy in general wards.