Objective: Although desire to die (DD) of varying intensity and permanence is frequent in patients with advanced cancer and those receiving palliative care, uncertainty exists concerning appropriate therapeutic responses to it. To support health professionals in dealing with patients´ potential DD, a training program and a semi-structured clinical interview guideline was developed. This study aimed for a revision of and consensus building on the clinical guideline to support proactively addressing DD and routine exploration of death and dying distress. Methods: Within a sequential mixed methods design, we invited 16 palliative patients to participate in semi-structured interviews and 377 (inter-)national experts to attend a two-round Delphi process. Interviews were analyzed using qualitative content analysis and an agreement consensus for the Delphi was determined according to predefined criteria. Results : 11 (69%) patients from different settings participated in face-to-face interviews. As key issues for conversations on DD they pointed out the relationship between professionals and patients, the setting and support from external experts, if required. A set of 149 (40%) experts (132/89% from Germany, 17/11% from 9 other countries) evaluated ten domains of the clinical guideline. There was immediate consensus on nine domains concerning conversation design, suggestions for (self-)reflection, and further recommended action. The one domain in which consensus was not achieved until the second round was “proactively addressing DD”. Conclusions : We have provided the first semi-structured clinical guideline to identify and address DD and to respond therapeutically – based on evidence, patients’ views and consensus among (inter-)national professional experts. Trial registration: German Clinical Trials Register (No. DRKS00012988).