Natalizumab treatment alters peripheral CD4 cells counts in multiple sclerosis (MS) patients, providing a way to monitor the pharmacodynamic effects of the drug. The study was undertaken to assess whether CD4 cell counts correlate with different phases of natalizumab treatment of relapsing MS patients, including during a 12-week planned treatment interruption, and whether that might provide insights on lymphocyte trafficking. Clinical outcomes, MRI data, and CD4 cell counts were assessed at baseline prior to initiating natalizumab, while on regular dosing, at the end of the 12-week extended dosing interval, and at the time of reinitiation of natalizumab. The 12-week interruption was well tolerated and not associated with return of MS activity, disability progression, or new or worsened MRI data. Observed significant shifts in CD4 counts - dramatically increasing from the baseline while on treatment and decreasing back to the baseline level off treatment, then rising in a similar manner on natalizumab reinitiation, suggest that these measurements may aid in monitoring modulation of lymphocyte trafficking and cell redistribution.