Stress ulcer prophylaxis (SUP) is commonly used in the intensive care unit (ICU), and is recommended in the Surviving Sepsis Campaign guidelines 2012. The present guideline from the Danish Society of Intensive Care Medicine and the Danish Society of Anesthesiology and Intensive Care Medicine sums up current evidence and gives clinical recommendations for SUP in the ICU. The GRADE approach was used for grading the evidence (www.gradeworkinggroup.org). In conclusion, existing meta-analyses have been underpowered to reach firm conclusions. We recommend not using SUP routinely for adult critically ill patients in the ICU outside the context of randomized controlled trials (GRADE 1C). No robust evidence supports recommendations for subpopulations in the ICU such as septic, burn, trauma, cardiothoracic or enterally fed patients. However, if SUP is considered clinically indicated in individual patients, we suggest using proton pump inhibitors over histamine-2-receptor antagonists (GRADE 2C)