OBJECTIVE: The objective of this study was to evaluate the resource consumption and outcomes associated with first-line monotherapy for community-acquired pneumonia (CAP), focusing specifically on the use of erythromycin, azithromycin, clarithromycin, and levofloxacin. METHODS: A retrospective database analysis was conducted of patients diagnosed with pneumonia from managed care organizations from January 1995 to April 2002. Linear and logistic regression models were used to examine associations with treatment success rates and direct medical costs between antibiotic treatments after controlling for patient demographics and pneumonia risk factors. RESULTS: Overall, treatment success rates were high (95.8%), the use of second antibiotics was uncommon (2.3%), and hospitalizations were infrequent (2.0%) among the 1952 patients studied. After controlling for patient characteristics and risk factors, statistically lower total costs were associated with erythromycin (92.7% lower), azithromycin (48.7% lower), and clarithromycin (21.3% lower) relative to levofloxacin, with no difference in treatment success between groups. Post-hoc analyses assessing subsets as 1) > 50 years of age; 2) presentation of a comorbid disease state; or 3) a chronic disease score (CDS) above the sample's mean indicated that both erythromycin and azithromycin were associated with statistically lower total costs than levofloxacin, while clarithromycin was not significantly different. When limiting the assessment to only newer agents, azithromycin (49.2% lower) and clarithromycin (21.7% lower) were associated with lower total costs relative to levofloxacin. Additionally, in subjects with a CDS above the sample's mean, only azithromycin was associated with lower total costs (49.2% lower) relative to levofloxacin, with no differences observed concerning treatment success. CONCLUSIONS: This real-world analysis of managed care patients found that erythromycin, azithromycin, and clarithromycin were associated with significantly lower total costs than levofloxacin, without differences in treatment success rates. Following stratification based upon various subset criteria, erythromycin and azithromycin were observed to have significantly lower total costs than levofloxacin.