In view of the continued reports of the rare occurrence of patients developing PML during natalizumab therapy, it is imperative to understand the clinical consequences of therapy discontinuation. Previous reports of outcomes after discontinuation of therapy suggested an eventual return of disease activity to pretreatment levels over 6 months but no evidence of rebound, with the possible exception of those patients stopping natalizumab therapy after a shorter treatment duration.6 Our cohort of 32 patients experienced near complete cessation of MRI and clinical disease activity, as well as significant improvement in daily symptoms, during natalizumab therapy even though they represent a group of patients who had disease refractive to multiple therapeutics before starting treatment. One-third of our patients developed an objectively defined exacerbation during therapy interruption or shortly after restarting natalizumab therapy, often associated with multiple cranial gadolinium-enhancing lesions and, in 3 cases tested, a cerebrospinal fluid pleocytosis. Patients experiencing a relapse during this interval tended to be younger with a shorter duration of natalizumab therapy prior to therapy interruption, although this was a modest finding. Importantly, the degree of inflammatory response (ie, gadolinium-enhancing lesion number) post–therapy interruption in those experiencing a relapse was correlated with the degree of inflammation prior to initiation of therapy and seemed to increase with duration of therapy interruption. This has important implications for the monitoring of patients during natalizumab therapy interruption. The inflammatory response was most notable in certain patients with SPMS, in whom we observed a large number of small to medium gadolinium-enhancing lesions distributed throughout almost all areas of involved brain and particularly noticeable along the edges of previous confluent T2 lesions and T1 black holes. Although we classified these individuals as having SPMS, those who experienced post–natalizumab therapy relapses were patients with moderately severe MS (significant disability for duration of disease, large T2 lesion burdens, and significant whole-brain atrophy) with a combination of progression, relapses, and gadolinium-enhancing lesions in the 2 years prior to natalizumab treatment. In 1 patient with SPMS (patient 1), a return of MRI activity 100 days following natalizumab therapy interruption continued to progress despite reinitiation of natalizumab therapy, culminating in a severe relapse with widespread inflammatory activity within 1 month of therapy restart. We believe it is unlikely that this relapse would have occurred without therapy interruption. First, this patient experienced complete cessation of all MS disease activity for 1.5 years prior to therapy interruption, despite significant evidence of disease activity prior to initiating natalizumab therapy (3 relapses in prior 2 years and 8 gadolinium-enhancing lesions at baseline). Second, there was no evidence of antinatalizumab antibodies on multiple evaluations prior to interruption of therapy or following the restart of therapy. Third, the return of disease activity on MRI that began during the interruption in therapy was associated with subtle evidence of clinical worsening by patient report that continued during the month following her therapy restart. She did not receive high-dose corticosteroid therapy until she was admitted to the hospital 1 month after therapy restart. A previous study reported that a single infusion of natalizumab did not enhance recovery from MS relapses and did not significantly decrease the number of gadolinium-enhancing lesions over 3 weeks compared with placebo, although there was a trend favoring a more rapid decrease in gadolinium-enhancing lesion number in the natalizumab treatment group.7 Another study reported 3 cases of severe relapse after the first infusion of natalizumab in patients with active RRMS.8 These authors suggested that an alteration of central nervous system regulatory networks by natalizumab therapy in this setting may worsen disease activity initially in some patients. This study as well as anecdotal experience suggest that a single dose of natalizumab monotherapy may not be effective at preventing continued progression of MS relapses, at least in some cases, and should be preceded by high-dose corticosteroid therapy to control the central nervous system inflammatory response prior to initiation of natalizumab therapy.