Clarithromycin is a macrolide antibiotic that is approved in Australia for a range of common infections, including community-acquired pneumonia (CAP). It is a potent inhibitor of the cytochrome P450 3A4 isoenzyme, and possibly p-glycoprotein. Clarithromycin has been associated with serious, potentially fatal drug interactions.[1, 2] Amoxycillin (for mild CAP) or benzylpenicillin (for moderate CAP) remain the recommended treatment for typical organisms, but guidelines for treatment of suspected atypical organisms have changed recently. For patients with suspected infection with atypical organisms in CAP, the Therapeutic Guidelines had previously recommended roxithromycin as first-line therapy. In the current edition, this was changed to doxycycline or clarithromycin as first- and second-line therapy respectively without mention of roxithromycin. We aimed to examine the potential for serious drug interactions in our patient population and the comparative effectiveness of roxithromycin by: (i) defining the prevalence of use of concomitant medications that could potentially interact with clarithromycin and (ii) reviewing the evidence comparing the use of roxithromycin against other established treatments.