The efficacy and safety of intravenous (i.v.) azithromycin followed by the oral form, given in addition to i.v. ampicillin-sulbactam, were evaluated in 151 patients hospitalized due to community-acquired pneumonia (CAP). Azithromycin 500 mg i.v. once daily plus ampicillin/sulbactam 3 g i.v. twice daily were administered for 2-5 days, then followed by oral azithromycin 500 mg once daily plus the same i.v. ampicillin/sulbactam regimen for a total of 7-10 days of treatment. The clinical response at day 14 was defined as cure, improvement or failure (with the addition of relapse at follow-up at day 30). The other efficacy measures included microbiological (eradication, presumed eradication, persistence, relapse, superinfection) and radiological (resolution, improvement, failure) findings, and outcome of signs and symptoms. Adverse events, vital signs and routine laboratory tests were the safety variables. The number and rate of patients with a positive clinical outcome at day 14 (cured + improved) in the intention-to-treat (ITT) analysis (n = 138) were 119 (86.2%), while 118 (87.4%) were cured or improved in the per-protocol population (PP) subset (n = 135). The rate of success at day 14 was slightly lower in the treated population (78.8%), which included all patients discontinued due to any cause. Clinical failures in the ITT population were 19 (13.8%) at day 14 and 1 (0.9%) at day 30, while 4 patients (3.6%) relapsed at day 30. Signs and symptoms of CAP improved from baseline to endpoint. The results in patients with a pathogen isolated at baseline in the cultures of respiratory tract secretions showed that 17 patients (77.3%) had eradication and 5 (22.7%) had presumed eradication (i.e. absence of adequate sputum for culture) at day 14, with no cases of persistence or superinfection. In the X-ray exam at day 30, 96 patients (85.0%) had resolution, 11 (9.7%) had improvement and 4 (3.5%) had failure. Treatment-related adverse events were reported in 10 patients (6.6%) and caused study discontinuation in 5 of them (one case of angioedema and one case of anaphylactic reaction were serious). No abnormal changes from baseline were found in laboratory parameters. Azithromycin i.v. followed by oral form given in addition to i.v. ampicillin/sulbactam was effective and well tolerated in patients with CAP who required hospital care.