Background. The community outbreak of legionnaires disease that occurred in Murcia, Spain, in July 2001—to our knowledge, the largest such outbreak ever reported—afforded an unusual opportunity to compare the clinical response of patients with Legionella pneumonia treated with levofloxacin with that of patients treated with macrolides and to determine the role of rifampicin combined with levofloxacin in treating severe legionellosis. Methods. An observational, prospective, nonrandomized study was conducted involving 292 patients seen at our hospital (Hospital “J. M. Morales Meseguer”; Murcia, Spain) who received a diagnosis of Legionella pneumonia during the Murcia outbreak. To compare both antibiotic regimens (macrolides vs. levofloxacin), patients were stratified by the severity of pneumonia. Duration of fever, clinical outcome, complications, side effects, and length of hospital stay were recorded. To assess the potential effects of adjuvant therapy with rifampicin, 45 case patients treated with levofloxacin plus rifampicin were evaluated and compared with 45 control pairs who were treated with levofloxacin alone. Results. With the exception of 2 patients who died, all patients were cured. There were no significant differences between treatment groups in clinical outcome for patients with mild-to-moderate pneumonia. Nevertheless, in patients with severe pneumonia, levofloxacin exerted superior activity; it was associated with fewer complications (3.4% of patients receiving levofloxacin experienced complications, compared with 27.2% of patients receiving macrolides; P =.02) and shorter mean hospital stays (5.5 vs. 11.3 days; P =.04). Addition of rifampicin to the treatment regimen for patients receiveing levofloxacin for severe pneumonia provides no additional benefit. Conclusions. Our findings strongly suggest that monotherapy with levofloxacin is a safe and effective treatment for legionnaires disease, including in patients with severe disease. In these patients, levofloxacin appears to be more effective than clarithromycin.