Daptomycin has demonstrated clinical efficacy in the treatment of methicillin-resistant Staphylococcus aureus-associated bacteremia and right-sided infective endocarditis. Although daptomycin is not approved for treatment of gram-positive pneumonia, clinical evidence suggests that it may be effective therapy for S. aureus-associated septic pulmonary emboli (SPE). We present our clinical experience with the use of daptomycin in combination with rifampin in four patients with SPE in the absence of infective endocarditis. Three of the patients had a history of injection drug use; two of these patients also had soft-tissue infections. All patients had clinical resolution of their infections. Daptomycin and rifampin appear to have a role in the treatment of methicillin-resistant S. aureus bacteremia with SPE in the absence of infective endocarditis and should be considered in patients that have failed therapy with vancomycin.