OBJECTIVES: The relatively low budget impact of orphan drugs is often used as an argument in reimbursement decisions. However, overall, the budget impact of orphan drugs can still be substantial. In this study, we assess the uptake and budget impact of orphan drugs in the Netherlands. METHODS: We examined the number of orphan drugs, the number of patients and budget impact of orphan drugs in the Netherlands in the period 2006 to 2012, both for inpatient and outpatient orphan drugs. Budget impact was provided in absolute numbers and relative to total pharmaceutical spending. RESULTS: The number of orphan drugs and patients treated increased substantially over the period studied. Overall, budget impact increased substantially over a period of six years, both in absolute terms (426% increase) as well as relative to total pharmaceutical spending (378% increase). Growth rates decreased over time. In 2012, 17% of available drugs had an individual budget impact of more than €10 million per year. CONCLUSIONS: Individual budget impact of orphan drugs is often limited, although exceptions exist. However, in total, the budget impact of orphan drugs is considerable and has grown substantially over the years. This could potentially influence reimbursement decisions for orphan drugs in the future.