As part of a larger open-label study (Ayres, J.G. et al. Allergy 2004; in press) of omalizumab (anti-IgE mAb) in patients with poorly controlled allergic asthma treated according to NHLBI 1997 guidelines, we retrospectively applied GINA 2002 severity criteria to define a population of patients with severe persistent asthma (>=step 3 clinical features [symptoms, FEV1] despite step 4 therapy), in addition to a history of emergency room visit or hospitalization plus >=1 course of oral steroids in the previous year. We evaluated the impact of omalizumab on clinically significant asthma exacerbation episodes (SAEEs) (requiring oral steroids). Patients were randomized to omalizumab plus best standard care (BSC) (n=101) or BSC alone (n=40) for 52 weeks. All patients were on inhaled steroids at baseline (mean 2822 µg/d BDP or equivalent), 93% were on long-acting β2-agonists, 36% on oral steroids, 40% on anti-leukotrienes. Omalizumab added to BSC reduced SAEE frequency vs BSC alone: 90% of patients on BSC alone had >=1 SAEE vs 61% of omalizumab patients (p<0.001). The mean annualized rate of SAEEs was reduced by 59% vs BSC alone (1.24 vs 3.00, p<0.001). Time to first SAEE (Kaplan-Meier) was longer for omalizumab vs BSC alone (median 344 vs 169 days, p<0.01). FEV1 (% pred) was higher in omalizumab patients throughout treatment (p<0.05). Omalizumab was well tolerated. Omalizumab provides significant benefits in the most severe asthma patients who continue to be poorly controlled despite GINA 2002 step 4 therapy.