Background: Depletion of B lymphocytes is a known therapeutic strategy for multiple sclerosis (MS) and related disorders. Ocrelizumab (OCR) is a humanized IgG1 monoclonal antibody (mAb) that targets the cell surface marker CD20 on pre-, immature-, mature- and memory-B cells. Rituximab (RTX) is a chimeric IgG1 anti-CD20 mAb that is often used, off-label, in the treatment of MS, neuromyelitis optica spectrum disorders (NMOSDs), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Both drugs can reduce circulating immunoglobulins (Ig) and increase the risk of infections over time. Growing evidence suggests that they also exert an indirect effect on circulating T cells. The interaction between age, sex, and alterations of circulating Ig or T cells over time while on treatment is unknown. Objectives: To characterize pre- and post-B-cell-depletion total and T lymphocyte counts, and serum Ig levels over time and correlate these immune markers with age, sex, and number of infections. Methods: Data from patients 18-75 years old who were receiving OCR or RTX for MS, NMOSD, or MOGAD between 07/01/2018 and 06/20/2020 and had laboratory values over 5 years were included in the analysis. Statistical analysis was performed using a repeated measures linear mixed model to account for variability in the timing of measurement and the multiple measures per patient. Results: A total of 157 patient charts were screened, and 95 (60.5%) met inclusion criteria. Follow-up duration was up to 62 months [range 2 62]. Mean (SD) for age was 45.8 (12.9), and 64 (66%) were females, 70 (72.2%) had MS, and 62 (63.9%) were on OCR. We observed a significant inverse interaction between age and while on treatment drop in total lymphocyte, CD4, CD8, and CD3 absolute counts. This interaction with age was not observed for the drop in Ig (IgM, IgG, IgA) observed in most patients. Lower IgG and IgA were associated with a higher frequency of reported infections. There was no significant interaction with sex and no difference in trends specific to treatment (OCR vs. RTX). Conclusions: Older patients receiving OCR or RTX are more likely to experience a drop in circulating T lymphocytes than their younger counterparts. The effect of age was not observed with Immunoglobulin decline. This suggests a differential interaction between age and adaptive vs. humoral immunity in patients receiving OCR or RTX.