At the time of this study, prior to the introduction of biologics in the US, systemic therapies used for the treatment of moderate-to-severe atopic dermatitis included off-label immunosuppressants and corticosteroids. Immunosuppressant therapy is associated with a substantial risk of side-effects, therefore needing clinical monitoring, and is likely to incur a significant healthcare burden for patients and payers. This retrospective cohort study based on claims data measured immunosuppressant use and its associated burden among US adult patients with atopic dermatitis covered under commercial or Medicare Supplemental insurance from January 01, 2010, to September 30, 2015. Overall, based on age, gender, region, and index year, 4201 control patients with atopic dermatitis without immunosuppressant use were matched with 4204 patients treated with immunosuppressants. The majority (68.5%) of patients using immunosuppressants were non-persistent with immunosuppressant treatment during the 12-month follow-up period after a mean (standard deviation) of 88.1 (70.7) days of immunosuppressant use; 72.3% required systemic steroid rescue treatment. Immunosuppressant users had higher incidence of immunosuppressant-related clinical events than controls; in addition, a larger proportion of immunosuppressant users versus controls developed cancer (0.28% vs 0.14%, respectively; P < 0.0001). Healthcare utilization and costs associated with clinical events and monitoring were also higher for immunosuppressant users compared with controls (total costs, $9516 vs $1630, respectively; P < 0.0001; monitoring costs, $363 vs $54, respectively; P < 0.0001). This study revealed that patients treated with systemic immunosuppressants often require systemic steroids or changes to treatment. The increase in immunosuppressant-related clinical events, including the need for increased monitoring with immunosuppressant treatment, compared with controls demonstrates a substantial treatment burden and highlights the unmet need for more effective long-term therapies for atopic dermatitis with improved safety profiles and reduced monitoring requirements.