Natalizumab treatment significantly reduced the annualised relapse rate and MRI activity over 2 years compared with placebo in phase III trials when administered as monotherapy in AFFIRM or in combination with interferon β-1a (IFNβ) in SENTINEL. The post hoc analyses reported here sought to determine the effect of natalizumab treatment on relapse activity in the minority of patients who continued to show MRI activity (ie, ≥1 gadolinium enhancing (Gd+) lesions or new or enlarging T2 hyperintense lesions) over 2 years in these trials. These analyses demonstrated that natalizumab treatment, both alone (AFFIRM) and in combination with IFNβ (SENTINEL), resulted in a reduced annualised relapse rate despite the presence of Gd+ lesions (p=0.004 and p=0.008, respectively) or new or enlarging T2 hyperintense lesions (each p<0.0001). Thus patients treated with natalizumab show clinical benefit even in the presence of continued MRI activity. Long term clinical outcome of these patients has not been studied.