Patients with B-non-Hodgkin lymphoma (NHL) are at increased risk of morbidity and mortality from SARS-CoV-2. We investigated the relationship between B cell cytopenia and the SARS-CoV-2 vaccine response in B-NHL patients. We measured anti-RBD antibodies and the lymphocyte immunophenotype in 19 controls, 22 lymphoma patients on observation (cohort 1) and 55 lymphoma patients receiving their vaccines post B-cell depleting therapy (cohort 2). Half of the lymphoma patients in both cohorts achieved seropositivity compared to 100% of controls. In cohort 2, only 5% achieved an antibody response in the first year post B-cell depleting treatment, vs 88% treated >2 years prior. Also, 28% of patients with <50 B cells/µl achieved a serologic response vs 86% of patients with B-cell >50 B cells/µl. B-cell cytopenia is profound within the first year of exposure to B-cell depleting treatment, therefore an additional dose of vaccine within that timeframe is unlikely to raise antibody levels.