People with asplenia/hyposplenism are at increased risk of fulminant sepsis, which carries a high mortality rate. A range of preventive measures is recommended although there is ongoing evidence that knowledge of and adherence to these strategies is poor. There have been significant changes in recommended vaccinations since the previously published recommendations in 2008. We provide current recommendations to help Australian and New Zealand clinicians in the prevention of sepsis in patients with asplenia and hyposplenia. The guideline includes Australian epidemiological data, preferred diagnostic techniques and recommendations for optimal antimicrobial prophylaxis and vaccination protocols.