OBJECTIVES: To examine treatment failure rates among community acquired pneumonia (CAP) patients treated with levofloxacin vs. macrolides (azithromycin, clarithromycin or erythromycin) in an outpatient setting. METHODS: A post-hoc, retrospective database analysis using eligibility (6-months pre and post), medical and pharmacy claims from a large US commercial health plan. Adults (=18) with an outpatient primary diagnosis of CAP between 01/01/2004 and 03/31/2005, and treated within 3 days of diagnosis with oral levofloxacin or macrolides were included. Patients with a recent hospitalization (10 days), prior antibiotic therapy (30 days), or immunocompromised state were excluded. Treatment failure was defined as receipt of receipt of renewal or alternative antibiotic claim, or hospitalization for CAP within 30 days of initial therapy. Multivariate logistic regression compared treatment failure rates between the two groups. Multivariate regression included all relevant variables describing patient characteristics including age, gender, region, Charlson comorbidity score, pre-existing respiratory, cardiovascular disease and diabetes. An identical sub-group analysis of patients =50 years old was conducted. RESULTS: Of 7526 CAP patients included, 2968 (39.4%) were treated with levofloxacin and 4558 (60.6%) with a macrolide. Levaquin patients were older (mean 48.7 vs. 43.7) and had a more severe Charlson comorbidity status (mean 0.40 vs. 0.25). Unadjusted treatment failure rates were 21.1% and 22.7% in levofloxacin and macrolide cohorts, respectively. After adjustment, compared to macrolides, levofloxacin patients were less likely to fail treatment (OR= 0.84, 95% CI: 0.73, 0.94, P=0.002). Of 2,967 subjects =50 years old, 21.8% of levofloxacin and 25.4% of macrolide patients failed treatment, respectively; likelihood of treatment failure was significantly lower for levofloxacin patients (OR=0.79, 95% CI: 0.66, 0.94, P=0.007). CONCLUSION: Compared with macrolides, Levofloxacin was associated with lower treatment failure rates in CAP patients treated in an outpatient setting. This difference was greater in patients =50 years old.