The evolution of COVID-19 as a global pandemic and emerging evidence from cohorts of patients have provided an immense opportunity to understand biological processes pertinent to development of the disease. The immune system is central to the development of characteristic hyperinflammation. In an attempt to understand the role of humoral immunity in COVID-19, reports encompassing patients with primary immunodeficiency (PID)(13 patients) and on B cell depletion therapies(39 patients) who had concurrent COVID-19 were reviewed. In PIDs, patients with common variable immunodeficiency had worse outcomes than patients with agammaglobulinemia. Among the patients on B cell depletion therapy, heterogenous outcome was seen. As a group, patients with multiple sclerosis had better outcomes as compared to patients with systemic autoimmunity. Further, increasing reports of autoimmunity and autoinflammatory diseases occurring in temporal relation to COVID-19 is also evidence for the pathogenic role played by B cells. B cell depletion in the setting of COVID-19 may not be harmful in all patients and in fact may be protective in some scenarios. Identification of risk factors associated with a worse outcome in patients on B cell therapy could provide a rationale for individualised management.