Background: Reduction in glucocorticoid exposure is the primary benefit of new biologic treatments in severe asthma, but there is currently no evidence that reduction in glucocorticoid exposure corresponds to a proportionate reduction in associated toxicity., Objectives: To use the validated Glucocorticoid Toxicity Index (GTI) to assess change in glucocorticoid toxicity after 12 months treatment with mepolizumab, and compare toxicity change to glucocorticoid reduction and change in patient-reported outcome measures (PROMs)., Methods: A longitudinal, real-world prospective cohort of 101 consecutive patients with severe asthma commenced on mepolizumab in a specialist UK regional severe asthma clinic. GTI toxicity assessment, cumulative glucocorticoid exposure and PROMs were recorded on commencing mepolizumab (V1), and after 12 months treatment (V2)., Results: There was significant reduction in oral glucocorticoid exposure (V1 median 4280 mg prednisolone per year (interquartile range 3083-5475 mg) versus V2 2450 mg prednisolone per year (1243-3360 mg), p<0.001). Substantial improvements in individual toxicities were observed, but did not correlate with oral glucocorticoid reduction. Mean±sd GTI aggregate improvement score (AIS) was -35.7±57.8 with a wide range in toxicity change at individual patient level (AIS range -165 to +130); 70% (71 out of 101) had a reduction in toxicity (AIS <0); 3% (three out of 101) had no change (AIS=0); and 27% (27 out of 101) an increase in overall toxicity. 62% (62 out of 101) of patients met the AIS minimally clinically important difference of ≤-10, but AIS did not correlate with glucocorticoid reduction or change in PROMs., Conclusion: Mepolizumab resulted in substantial oral glucocorticoid reduction, but this did not correlate with reduction in oral glucocorticoid toxicity, which varies widely at the individual patient level. Oral glucocorticoid reduction is not a comprehensive measure of response to mepolizumab., Competing Interests: Conflict of interest: P.J. McDowell reports personal fees for lectures from GlaxoSmithKline, outside the submitted work. Conflict of interest: J.H. Stone reports that the Massachusetts General Hospital owns the copyright to the Glucocorticoid Toxicity Index. Conflict of interest: Y. Zhang has nothing to disclose. Conflict of interest: K. Honeyford has nothing to disclose. Conflict of interest: L. Dunn has nothing to disclose. Conflict of interest: R.J. Logan has nothing to disclose. Conflict of interest: L.P.A. McGarvey reports personal fees for lectures and advisory board work from GlaxoSmithKline, personal fees for lectures and advisory board work, and non-financial support from Chiesi, outside the submitted work. Conflict of interest: C.A. Butler reports other (conference registrations) from Chiesi and Napp, personal fees for lectures from GlaxoSmithKline, personal fees for lectures and advisory board work from AstraZeneca, outside the submitted work. Conflict of interest: L.G. Heaney reports non-financial support from GlaxoSmithKline, during the conduct of the study; grants from Amgen, AstraZeneca, Medimmune, Janssen, Novartis, Roche/Genentech, GlaxoSmithKline plc., Boehringer Ingelheim, Aerocrine and Vitalograph, other (support for advisory board work/lectures) from Novartis, Hoffman la Roche/Genentech Inc, Evelo Biosciences, Sanofi, GlaxoSmithKline, AstraZeneca, Teva, Theravance and Circassia, other (travel funding support to attend meetings; institution renumerated) from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK and Napp Pharmaceutical, other (project grant funding) from Medimmune, Novartis UK, Roche/Genentech and GlaxoSmithKline plc., other (clinical trials for which his institution was remunerated) from AstraZeneca, GlaxoSmithKline, Schering Plough, Synairgen, Novartis and Roche/Genentech, outside the submitted work., (Copyright ©The authors 2022.)