Background <p>A serious illness conversation elicits a patient’s wishes, goals and values in the setting of advancing illness. Patients living with structural vulnerabilities and substance use disorders encounter barriers to these conversations and therefore often experience less than ideal deaths. This study aims to understand the needs and preferences of these patients during serious illness conversations in the acute hospital setting and to inform best practice recommendations for serious illness conversations with this patient population.</p> Methods <p>We performed a qualitative research study using interpretive description methodology at a single tertiary care inner-city hospital in Vancouver, British Columbia, Canada. Data was collected from 16 hospitalized participants living with structural vulnerability, substance use disorder and chronic illness. Semi-structured interviews were recorded, transcribed and analyzed iteratively by our research team using thematic analysis.</p> Results <p>Participants had unmet basic needs and therefore unique priorities during serious illness conversations. Participants frequently had previous negative healthcare experiences which resulted in them guarding their feelings from healthcare providers. Hope was emphasized as an important component of serious illness conversations. Participants also outlined specific preferences and recommendations for healthcare providers engaging in these conversations.</p> Conclusions <p>Our findings offer several important considerations for engaging in serious illness conversations with patients living with structural vulnerabilities and substance use disorders that, if implemented, should improve the quality of conversations and care.</p>