The human thymus is susceptible to viral infections that can severely alter thymopoiesis and compromise the mechanisms of acquired tolerance to self-antigens. In humans, plasma cells residing primarily in the bone marrow confer long-lasting protection to common viruses by secreting antigen-specific antibodies. Since the thymus also houses B cells, we examined the phenotypic complexity of these thymic resident cells and their possible protective role against viral infections. Using tissue specimens collected from subjects ranging in age from 5 days to 71 years, we found that starting during the first year of life, CD138+ plasma cells (PC) begin accumulating in the thymic perivascular space (PVS) where they constitutively produce IgG without the need for additional stimulation. These, thymic PC secrete almost exclusively IgG1 and IgG3, the two main complement-fixing effector IgG subclasses. Moreover, using antigen-specific ELISpot assays, we demonstrated that thymic PC include a high frequency of cells reactive to common viral proteins. Our study reveals an unrecognized role of the PVS as a functional niche for viral-specific PCs. The PVS is located between the thymic epithelial areas and the circulation. PCs located in this compartment may therefore provide internal protection against pathogen infections and preserve the integrity and function of the organ.