Introduction Real-world data on Omalizumab (OMA) and Mepolizumab (MEPO) can inform their use in severe asthma (SA). We studied patients in the Wessex AsThma CoHort of difficult asthma (WATCH) to: 1. Phenotypically compare OMA or MEPO treated patients against a SA, non-biologic group (SNB). 2. Assess clinical responses to OMA and MEPO. 3. Assess the spectrum of responses to these biologics. Methods We retrospectively phenotyped biologic naïve patients from WATCH (N=478) commenced on OMA (N=105) or MEPO (N=62) compared to SNB (N=178). Biologic response was gauged using standard criteria and response features were identified using logistic regression. Results OMA and MEPO patients were phenotypically distinct. Both drugs significantly reduced exacerbations, acute healthcare encounters (emergency department or hospital admissions), maintenance oral corticosteroid dose, and improved Asthma Control Questionnaire 6 (ACQ6) scores. OMA patients with more exacerbations at baseline (P=0.024), less acute healthcare encounters (P=0.050), and no anxiety (P=0.008) were more likely to respond to it. Lower baseline ACQ6 was independently associated with higher odds of MEPO response (P=0.007). Combined (OMA or MEPO) non-responders had significantly more psychological co-morbidities and worse baseline subjective disease markers compared to responder groups. Current criteria used to measure trial outcomes for MEPO, but not OMA, missed some modalities of response. Conclusion In a difficult asthma cohort, OMA and MEPO were used for distinct SA phenotypes, yet both were multidimensionally efficacious. Among these phenotypes, some clinical features associated with response were identified which emphasized the importance of addressing treatable traits when considering biologic therapy.