BACKGROUND: Expert national/global asthma management recommendations raise the issue whether a safe threshold of short-acting β(2)-agonist (SABA) use without concomitant inhaled corticosteroids (ICS) exists. OBJECTIVE: To examine SABA and maintenance therapy associations with severe asthma exacerbations across North America and Europe. METHODS: Observational analyses of 10 SABa use IN Asthma (SABINA) datasets involving 1,033,564 patients (≥12 years) from Canada, France, the Netherlands, Poland, Spain, United Kingdom (UK), and United States (US). Negative binomial models (incidence rate-ratio [95% confidence interval]) adjusted for prespecified-covariates]) evaluated associations between SABA and exacerbations. RESULTS: Across severities, 40.2% of patients were prescribed/possessed ≥3 SABA canisters/year. Per GINA-2018 definitions, step 3‒5-treated patients prescribed/possessing ≥3 vs. 1‒2 SABA experienced more severe exacerbations (between 1.08 [1.04‒1.13], US-Medicare; 2.11 [1.96‒2.27], Poland). This association was not observed in all step 1‒2-treated patients (the Netherlands 1.25 [0.91‒1.71]; US-commercial 0.92 [0.91‒0.93]; US-Medicare 0.74 [0.71‒0.76]). We hypothesize that this inverse association between SABA and severe exacerbations in the US datasets was attributable to the large patient population possessing <3 SABA and no maintenance therapy and receiving oral corticosteroid bursts without face-to-face healthcare provider encounters. In US SABA monotherapy-treated patients, ≥3 SABA was associated with more emergency/outpatient visits and hospitalizations (1.31 [1.29‒1.34]). Most GINA 2‒5-treated study patients (60.6%) did not have maintenance therapy for up to 50% of the time; however, the association of ≥3 SABA and severe exacerbations persisted (1.32 [1.18‒1.49]) after excluding these patients and the independent effect was further confirmed when UK SABA data was analyzed as a continuous variable in patients with up to 100% annual coverage for ICS-containing medications. CONCLUSIONS: Increasing SABA exposure is associated with severe exacerbation risk, independent of maintenance therapy. As addressed by GINA, based on studies across asthma severities where as-needed fast-acting bronchodilators with concomitant ICS decrease severe exacerbations compared with SABA, our findings highlight the importance of avoiding a rescue/reliever paradigm utilizing SABA monotherapy.< Réduire