Background: Certain DMTs may negatively impact the humoral response to SARS-COV-2 vaccines. However, many MS-related clinical, demographic, and immunological variables can potentially impact vaccine response and those variables have not been fully explored. Objectives: to compare clinical, demographic, and immunological variables in MS patients with positive versus negative spike protein antibody following SARS-COV-2 vaccination Methods: patients with MS and related neuroimmunological disorders who requested verification of the immune response to the SARS-COV-2 vaccine were tested for the spike protein antibody between January and September of 2021. We carried out an exploratory analysis to compare patients with positive versus negative spike protein antibody. Results: Forty patients (mean age 53+/-11, 77% females) were included. There were 22 patients with positive post-vaccination spike protein antibody (55%) and 18 with negative antibody (45%). Patients with negative antibody were more likely to have been on B-cell therapy (83% vs 32%, P=.001) while positive patients were more likely to have been on a fumarate (36% vs 5.5%, P=.02). There was no difference between the two groups in the utilization of S1P1 modulators or non-selective immunosuppressants, gender, age, race, disease phenotype, vaccine brand, and lymphocyte counts. Half the positive patients on fumarates had lymphopenia at the time of vaccination but none below 0.8X109/L. Among patients on B-cell therapy, 32% had a positive spike protein antibody and were more likely to have detectable CD19 cells at the time of vaccination compared to those with negative antibody (P=0.04). There was no statistically significant difference between the two subgroups in terms of vaccine timing relative to B-cell therapy dose or the presence of hypogammaglobinemia. None of the patients with or without spike protein antibody had post-vaccination COVID19 infection. Conclusions: B-cell therapy is associated with a negative humoral response to SARS-COV-2 vaccines but patients with detectable CD19 counts at the time of vaccination are more likely to have a positive humoral response. Hypogammaglobinemia and vaccine timing were non-influential. The fumarates are associated with positive humoral response even in the presence of mild lymphopenia. Both positive and negative humoral responses were equally seen in patients on S1P1 modulators and non-selective immunosuppressants but the number of those patients was small.