Discrepancies between registered prescriptions and patients' actual use of medications are described as frequent and often resulting in adverse medication events. We aimed to assess the extent of and causes behind discrepancies between medications listed in the Danish national prescription system (Shared Medication Record) and patients' actual use of medications. We prospectively reconciled medication for 260 consecutively admitted polypharmacy patients (>50 years and ≥5 prescriptions) at two hospitals in the Capital Region of Denmark. The type of discrepancies were determined and the cause of the discrepancies were evaluated as primarily caused by (1) the patient (i.e., intentional or unintentional non-adherence) or (2) the health care system (i.e., lack of appropriate update of the SMR by physicians in primary or secondary care). There was a median of 12 [IQR 9–15] medications listed and 3 [IQR 1–5] medication discrepancies per patient (total n = 925). The majority (53%) of discrepancies were caused by the health care system, 32% were caused by the patients, of which 70% were intentional non-adherence, and 15% had an indeterminable cause. In conclusion, discrepancies between medications listed in the Shared Medication Record and actual use of medications were frequent and were most often caused by clinicians not updating the prescription information.