Off-label prescription is part of routine care in palliative medicine, but no information is available about the situation in Italy. A cross-sectional observational survey was undertaken on all 66 Italian palliative care freestanding inpatient units to describe off-label prescriptions. Data were collected on 507 patients. Each prescribed drug was matched with Italian Marketing Authorization indications: 159 drugs off-label (4.5% of all prescribed drugs) for the stated indication were given to 128 patients (25.2%), and drugs unlicensed for subcutaneous injection were given to 147 patients (85.4% of all subcutaneous prescriptions, excluding insulin and heparin). The off-label prescriptions were subsequently evaluated by referring to the Italian National Pharmaceutical Formulary (INPF) and the British Palliative Care Formulary (PCF2). Although drugs are frequently prescribed off-label in inpatient palliative care units in Italy, this strategy was not always backed by clinical evidence, and in some cases, official/authoritative sources, such as INPF and PCF2 did not support it. Clinical trials and/or agreed international guidelines are needed to support the off-label use of the most widely prescribed drugs in palliation.