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Objective: To investigate the perception of self-isolation at home in patients with cancer during the lockdown period resulting from the COVID-19 outbreak in Italy. Methods: A cross-sectional descriptive study was conducted through an online survey of patients with cancer who were sheltering at home from 29th March to 3rd May 2020. Perception of self-isolation was assessed using the ISOLA scale, after evaluation of its psychometric properties. Content analysis was used to analyse two open-ended questions. Results: The participants were 195 adult patients with cancer (female = 76%; mean age = 50.3 ± 11.2; haematological malignancy = 51.3%). They reported moderate isolation-related suffering (M = 2.64 ± 0.81), problems in their relationships with others (M = 3.31 ± 1.13) and difficulties in their relationships with themselves (M = 3.14 ± 1.06). Patients who experienced significantly more social problems were older, had less education and were living without minor children. Overall, four main categories emerged from the qualitative content analysis: (1) lack of freedom and social life, (2) uncertainty and worries, (3) feeling supported and (4) dealing with isolation. Conclusion: Living with cancer in the COVID-19 pandemic was often perceived as an isolating experience, primarily in terms of detachment from loved ones.