Rationale: Clinical remission is a multicomponent treatment goal in severe asthma. However, only about 30% of patients achieve clinical remission when treatment decisions are guided using blood eosinophil counts and fractional exhaled nitric oxide concentrations. Objectives: To assess the effectiveness of a comprehensive, individualized treatment strategy in achieving clinical remission over 24 months in patients with severe asthma. Methods: Treatment strategies-including antiinflammatory therapies, biologics, antibiotics, immunomodulators, and bronchial thermoplasty-were guided by clinical assessment, airway physiology, airway inflammometry, and bioimaging. Clinical remission was defined as no exacerbations for 24 months, no oral corticosteroid use, and partly/well-controlled symptoms, with or without lung function criteria. Measurements and Main Results: A total of 178 patients with severe asthma were evaluated. Of these, 88.2% were treated with biologics alone or in combination with other strategies; 20.2% were treated with antibiotics, hypertonic saline, and/or immunoglobulins; and 9% underwent bronchial thermoplasty after controlling the inflammatory component. After 24 months, 89.9% of patients were exacerbation-free, 83.1% were oral corticosteroid-free, 78.1% had partly/well-controlled symptoms, and 85.4% had preserved lung function. Clinical remission was achieved in 66.3% of patients based on the three primary criteria and in 61.6% when including FEV1% decline ⩽5% from baseline. However, when the most stringent criteria were applied (five-point Asthma Control Questionnaire ⩽0.75 and FEV1 ⩾80%), the clinical remission rate was 29.1%. Residual disease activity was driven primarily by airway infections and airway hyperresponsiveness rather than type 2 inflammation. Conclusions: By using a comprehensive set of biomarkers and a management strategy tailored to individual pathobiology, a high proportion of patients with severe asthma can achieve clinical remission, depending on the definitions used. Nonetheless, recurrent airway infections, mucus, and airway hyperresponsiveness remain key unmet needs in severe asthma.