Background: Atopic dermatitis (AD) has been linked to systemic infections in adulthood, but large-scale studies are few, and potential associations are unclear. Objective: To examine whether adults with AD have increased risk of developing systemic infections leading to hospital-based management. Methods: Nationwide register-based cohort study including all Danish adults from 1995 through 2017. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated by using Cox models. Results: A total of 10,602 adults with AD (median age, 29.8 y; interquartile range, 22.6-44.8) and 106,020 reference individuals were included. The overall incidence rate per 10,000 person-years of systemic infections was 180.6 (95% CI, 172.6-189.0) among adults with AD compared with 120.4 (95% CI, 118.3-122.5) among reference adults. The association between AD and systemic infections was observed for musculoskeletal (adjusted HR [aHR], 1.81; 95% CI, 1.42-2.31), heart (aHR, 1.75; 95% CI, 1.21-2.53), and upper (aHR, 1.42; 95% CI, 1.15-1.73) and lower respiratory tract infections (aHR, 1.21; 95% CI, 1.10-1.33). The risk of sepsis (aHR, 1.19; 95% CI, 1.01-1.44) and skin infections (aHR, 2.30; 95% CI, 2.01-2.62) was also increased. Limitations: The findings cannot be generalized to adults with milder AD seen outside the hospital system. Conclusion: We found an increased risk of systemic infections among adults with hospital managed AD.