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Background: Treatment of moderate-to-severe atopic dermatitis (AD) can be challenging and little is known about the sustainability of on- and off-label prescribed systemic therapies. Objectives: To compare drug survival (DS) rates and reasons for drug discontinuation of cyclosporine A (CyA), dupilumab (DUP), azathioprine (AZA), methotrexate (MTX) and mycophenolate mofetil (MMF) prescribed under real-world conditions. Materials & Methods: In this retrospective study, 139 treatment courses for 94 adults with AD treated at two German dermatology departments were analysed. Results: Based on Cox regressions with CyA as reference category, hazard ratios for treatment discontinuation were 0.10 for DUP, 0.87 for MTX, 0.98 for MMF, and 1.18 for AZA. CyA, AZA, and MTX were most frequently interrupted due to adverse events, and MMF due to non-compliance. Only one patient (6.3%) discontinued DUP before the end of the observation period, which was due to ineffectiveness. Conclusion: Systemic therapies for AD differ with regards to DS and reasons leading to treatment withdrawal; this should be considered in real-life practice.