Longterm macrolide therapy has been reported to be effective in treating chronic lower respiratory tract infections (CLRTIs). In this context, erythromycin and clarithromycin are usually used for this purpose. However, refractory cases are occasionally encountered, thereby indicating a major problem pending. In the present study, we administered azithromycin to three patients with CLRTIs whose clinical course had been unsatisfactory with longterm therapy of either erythromycin or clarithromycin. Following longterm therapy with azithromycin, both the incidence of acute exacerbations and the sputum volume were decreased. A significant change in the sputum flora was observed, without obvious side effects; however, no improvement was evidenced in the findings on flow volume curve tests and arterial blood gas analysis. In advanced disease, longterm azithromycin therapy may be as effective as that with erythromycin or clarithromycin; in our view, however, its efficacy may be limited, and large-scale clinical trials are required to determine the most suitable macrolide for the treatment of CLRTIs.