Introduction Anti-interleukin-5/5Ra therapy has shown to reduce maintenance oral corticosteroid dose in severe eosinophilic asthma. However, the effect on cumulative oral corticosteroid exposure is currently unknown. Neither is it known how prior oral corticosteroid exposure affects response to anti-interleukin-5/5Ra treatment. We aimed primarily to compare the cumulative oral corticosteroid exposure over a 2-year period before and after anti-interleukin-5/5Ra initiation, and secondarily to investigate whether duration and cumulative oral corticosteroid exposure prior to anti-interleukin-5/5Ra influence the ability to discontinue oral corticosteroids within 2 years of anti-interleukin-5/5Ra therapy. Methods This real-world nationwide observational registry-based study evaluated all dispensed oral corticosteroids from 389 adults with severe eosinophilic asthma included in the Dutch severe asthma registry (RAPSODI) 2 years before and 2 years after initiating anti- interleukin-5/5Ra. Wilcoxon-signed rank test and multivariable regression analyses were used. Results Median (IQR) cumulative oral corticosteroid exposure in the 2 years before and after anti-interleukin-5/5Ra initiation decreased from 2.715 g (1.150-5.539) to 1.050 g (0.300-3.640), p<0.001. Fifty-two percent of patients were able to discontinue oral corticosteroids within 2 years anti-interleukin-5/5Ra therapy, which was independently predicted by lower and shorter prior oral corticosteroid exposure. Conclusion This real-world study showed that anti-interleukin-5/5Ra therapy leads to a significant reduction in cumulative oral corticosteroid exposure over a 2-year period. Patients with lower and shorter oral corticosteroids exposure were more likely to completely eliminate oral corticosteroids. Since cumulative exposure increased progressively prior to anti-interleukin-5/5Ra initiation, our data suggest that early intervention leads to a better long-term prognosis in patients with severe eosinophilic asthma.