Background: Evidence on long-term dupilumab treatment for atopic dermatitis in daily practice is lacking. Objective: To investigate patient characteristics, treatment aspects, effectiveness, and safety of up to 84 weeks of dupilumab treatment. Methods: An observational prospective cohort study was conducted of patients with atopic dermatitis starting dupilumab in routine clinical care. Results: Of the 221 included patients, 103 used systemic therapy at baseline. At 84 weeks, we found a change of −15.2 (SE, 1.7) for the Eczema Area and Severity Index, −16.9 (SE, 1.4) for the Patient-Oriented Eczema Measure, and −17.2 (SE, 1.6) for the Dermatology Life Quality Index. We found a trend for improvement over time for the Investigator Global Assessment and Numerical Rating Scale for pruritus. Severe (n = 79) including serious (n = 11) adverse events were observed in 69 patients. Eye complaints were most frequently reported (n = 46). Twenty-one patients adjusted the regular dosing schedule, and 14 patients discontinued treatment, mainly due to ineffectiveness (n = 7). Limitations: Only adverse events of severe and serious nature were registered for feasibility reasons. Conclusion: Daily practice dupilumab treatment of up to 84 weeks is generally well-tolerated, apart from the reporting of eye complaints. It can be considered a long-term effective treatment for atopic dermatitis in combination with topical and initial concomitant systemic treatment, showing a sustained improvement of signs, symptoms, and quality of life.