This retrospective matched-cohort analysis compared health-economic burdens of adults (≥18 years; n = 377) with phenylketonuria (PKU) and age/gender-matched non-PKU controls (n = 3770) in Germany. Healthcare costs and resource-utilization were analyzed for the year 2015. Differences between groups were tested using 95% CI of mean differences (MD). PKU patients had significantly higher mean costs in total (MD €3307, 95% CI €1736–€4879), for pharmaceuticals (MD €1912, 95% CI €1195–€2629) [including dietary amino-acid supplements (MD €1268, 95% CI €864–€1672)], and outpatient costs (MD €395, 95% CI €115–€675). Inpatient costs (MD €904, 95% CI -€293 to €2100) and costs for aids and remedies (MD €97, 95% CI -€10 to €203) were also higher in PKU patients. PKU patients had more outpatient visits and stayed longer in hospital. Adult PKU patients incur higher total healthcare costs than non-PKU controls, especially regarding pharmaceuticals and outpatient costs, and more frequent resource-utilization, resulting in higher health-economic burden for the statutory healthcare system.