Background: Mixtures of fumaric acid esters (FAE) are used as an oral systemic treatment for moderate to severe psoriasis. Large clinical studies with dimethylfumarate (DMF) monotherapy are scarce. Objectives: The objective of this study is to assess the effectiveness and long-term safety of high-dose DMF monotherapy in moderate to severe psoriasis. Methods: A prospective single-blinded follow-up study was performed in a cohort of patients treated with DMF. Patients were followed-up at fixed intervals. Assessment of consecutive photographs was performed by two observers. Primary outcome was a change in static physician global assessment (PGA) score. Safety outcome was defined as incidences of (serious) adverse events. Results: A total of 176 patients with moderate to severe psoriasis were treated with DMF for a median duration of 28 months. The median daily maintenance dosage of 480mg was reached after a median of 8 months. Psoriasis activity decreased significantly by 1.7 out of five points. A total of 152 patients reported one or more adverse events, such as gastrointestinal complaints and flushing. Conclusions: High-dose DMF monotherapy is an effective and safe treatment option in moderate to severe psoriasis. It can be suggested that 50% of all patients may benefit from high-dose DMF monotherapy.