Background <p>Multi-cancer detection (MCED) blood tests have the potential to screen for early-stage cancers. Understanding how people experience an MCED cancer signal result is vital prior to any future implementation. We explored experiences in a trial context.</p> Methods <p>A subset of 41 participants in the NHS-Galleri trial (NCT05611632), with a cancer signal detected result, were interviewed. We selected: 20 participants with cancer found (self-reported) and 21 without cancer (following tests). Transcripts were analysed thematically.</p> Results <p>Expectations of cancer played a pivotal role in emotional, cognitive and social responses, and were influenced by participants’ experiences of health and symptoms. While the cancer signal was often unexpected, the predicted cancer signal origin made sense when consistent with family history or health issues. During the period of diagnostic uncertainty, views of healthiness or lack of family history were sometimes used to self-reassure. For some, a cancer diagnosis was unexpected; for others, expectations of cancer had gradually increased. For those without cancer, believing that it could be present affected their sense of reassurance.</p> Discussion <p>Information about the meaning of a cancer signal will be needed if MCED screening is implemented. Patient support could be designed around their expectations of cancer at each stage.</p>