Background: Dimethyl fumarate (DMF) depletes CD8+ and CD4+ T cells, and cases of herpes zoster (HZ) in patients with multiple sclerosis (MS) on DMF have been documented. Objectives: To evaluate lymphocyte subsets in patients with MS who developed HZ on DMF (Tecfidera) compared to matched controls who did not develop HZ. Methods: We used linear mixed-effects models to test for differences in white blood cell count, lymphocyte percentage, absolute lymphocyte count, CD3+ percentage, absolute CD3+ count, CD4+ percentage, absolute CD4+ count, CD8+ percentage, absolute CD8+ count, and CD4+:CD8+ ratio over time in HZ and non-HZ groups. Results: Eighteen patients developed HZ while on DMF. The linear mixed-effects model for CD4+:CD8+ ratio showed a significant difference between the HZ and non-HZ groups (p = 0.033). CD4+:CD8+ ratio decreased over time in the HZ group and increased over time in the non-HZ group. Conclusion: Patients with MS who develop HZ while on DMF have high CD4+:CD8+ ratios, suggesting an imbalance of CD4+ and CD8+ cells that may put a patient at risk for developing HZ while on DMF. This result emphasizes the need for lymphocyte subset monitoring (including CD4+:CD8+ ratios) on DMF, as well as vaccination prior to DMF initiation.