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Unmet needs for advanced-disease cancer patients are fatigue, pain, and emotional support. Little information is available about the feasibility of interventions focused on patient-reported outcome measurement developed according to the Medical Research Council (MRC) Framework in advanced-disease cancer patients. We aimed to pilot a nurse-led complex intervention focused on QoL assessment in advanced-disease cancer patients. The INFO-QoL study was based on an exploratory, nonequivalent comparison group, pre-test-post-test design. Study sites received either the INFO-QoL intervention or usual care. Adult advanced-disease cancer patients admitted to hospice inpatient units that gave their informed consent were included in the study. Subjects were 187 patients and their families and 19 healthcare professionals. We evaluated feasibility, acceptability, and patients' outcomes using the Integrated Palliative Care Outcome Scale. Nineteen healthcare professionals were included. The mean competence score increased significantly over time (p < 0.001) and the mean usefulness score was high 8.63 (± 1.36). In the post-test phase, 54 patients were allocated to the experimental unit and 36 in the comparison unit. Compared to the comparison unit, in the experimental unit anxiety (R2 = 0.07; 95% CI = −0.06; 0.19), family anxiety (R2 = 0.22; 95% CI = −0.03; 0.41), depression (R2 = 0.31; 95% CI = −0.05; 0.56) and sharing feelings (R2 = 0.09; 95% CI = −0.05; 0.23), were improved between pre-test and post-test phase. The INFO-QoL was feasible and potentially improved psychological outcomes. Despite the high attrition rate, the INFO-QoL improved the quality and safety culture for patients in palliative care settings. • The INFO-QoL intervention was feasible, acceptable, and improved family anxiety, depression, and sharing feelings. • The INFO-QoL intervention is innovative because it is based on addressing patients' outcomes by a nurse-led intervention. • The improved psychosocial needs were significantly associated with an increased number of actions delivered by the team. • QoL assessment interventions are complex and under this perspective they may ensure better evidence-based practice. • Nurse-led interventions have a holistic view of patients' outcomes, and a patient/family-centered care-oriented culture. [ABSTRACT FROM AUTHOR]