Although serious infections such as bacterial endocarditis (BE) are being increasingly treated with parenteral antibiotics via Hospital-in-the-Home (HITH) programmes in Australia, there are few published data to confirm the safety and efficacy of this treatment modality, especially among patients with BE due to pathogens other than streptococci. In a 12-month prospective, multi-site study we assessed HITH treatment outcomes for all cases of BE. Among the 40 BE cases (29 'definite', 11 'possible'; Duke criteria) caused by a range of pathogens (16 staphylococci spp., 11 streptococci, 4 other, 9 culture-negative), cure was achieved in 37 (93%) cases. BE due to Staphylococcus aureus was significantly associated with an inferior outcome (p =0.046). Adverse events were relatively common (9/40), but most were not severe and were managed with continuation of HITH care. BE can be safely managed via HITH, but particular care in patient selection is necessary, especially for cases due to S. aureus.