Background: Phenylketonuria is a well-known disease, yet the characteristics of the affected population and their use of healthcare resources have not been comprehensively evaluated. Patient characteristics and use of resources are subjects of interest for most governments, especially for a disease included in newborn screening programs. Objective: The aim of this study was to determine characteristics and use of healthcare resources of patients with phenylketonuria in the region of Catalonia. Methods: Records of 289 patients admitted with phenylketonuria between 2007 and 2017 were extracted from the PADRIS database that includes admission data from primary care centers, hospitals (inpatient and outpatient care), extended care facilities, and mental health centers. Results: The patient population was composed of 140 male patients and 149 female patients, and 102 patients were registered via newborn screening during the study period. Patients were admitted on average 2.19 times per year, mostly into primary care centers which concentrated the largest portion of direct medical expenses. Similar percentages of urgent and scheduled admissions were registered both in primary care and hospitals. Annual direct medical cost of treating patients with phenylketonuria was €667 per patient. Finally, 66.80% of the patients suffered from chronic conditions affecting two or more systems, likely to correspond to a wide variety of conditions. Conclusions: Altogether, phenylketonuria patient demographics and direct medical costs in Catalonia have been revised. Patients diagnosed with phenylketonuria appeared 1.3-times more likely to suffer from chronic conditions in distinct organ systems, which is expected to have an effect on their use of healthcare resources. These results support the need to adapt and improve the healthcare system, taking multimorbidity into consideration in an effort to control the medical expenses derived.