BACKGROUND Effectiveness of biologics has neither been established in patients with high oral corticosteroid exposure (HOCS), nor been compared to effectiveness of continuing with HOCS alone. OBJECTIVE To examine the effectiveness of initiating biologics in a large, real-world cohort of adult patients with severe asthma and HOCS. METHODS This was a propensity-score-matched, prospective cohort study using data from the International Severe Asthma Registry (http://isaregistries.org/). Between January 2015 and February 2021, patients with severe asthma and HOCS (long-term OCS ≥1 year or ≥4 courses of rescue OCS within a 12-month period) were identified. Biologic initiators were identified and, using propensity scores, matched 1:1 with non-initiators. The impact of biologic initiation on asthma outcomes were assessed using generalized linear models. RESULTS We identified 996 matched pairs of patients. Both groups improved over the 12-month follow-up period, but improvement was greater for biologic-initiators. Biologic initiation was associated with a 72.9% reduction in the average number of exacerbations/year versus non-initiators (0.64 vs 2.06, rate ratio: 0.27 [95%CI, 0.10, 0.71]). Biologic initiators were 2.2 times more likely than non-initiators to take a daily long-term OCS dose <5mg (probability: 49.6% vs 22.5%; p=0.002) and had a lower risk of asthma-related emergency department visits (relative risk: 0.35 [95% CI: 0.21, 0.58]; rate ratio 0.26 [0.14, 0.48]) and hospitalizations (relative risk: 0.31 [95% CI: 0.18, 0.52]; rate ratio 0.25 [0.13, 0.48]). CONCLUSIONS In a real-world setting, including patients with severe asthma and HOCS from 19 countries, and within an environment of clinical improvement, initiation of biologics was associated with further improvements across multiple asthma outcomes, including exacerbation rate, OCS exposure, and healthcare resource utilization.