During infection, Cryptococcus neoformans capsular glucuronoxylomannan (GXM) is released into tissues, where it may be associated with a variety of deleterious immunological effects. Relatively little is known about the organ distribution and cellular localization of GXM antigen. Intravenous administration of GXM to rats resulted in persistent serum levels which declined with a half-life of 14.3 h in the first 74 h and 3 h thereafter, coincident with the appearance of serum antibodies to GXM. GXM was sequestered primarily in spleen tissue, with localization to marginal zone and follicular cells. Administration of the murine immunoglobulin G1 monoclonal antibody (MAb) 2H1 resulted in > 99% reduction in serum GXM level within 3 h. MAb 2H1 administration resulted in liver GXM deposition, with cellular localization primarily to Kupffer cells. GXM was also found in the spleens of MAb 2H1-treated rats, with localization to the marginal zones and follicles. Endotracheal administration of GXM resulted in low serum levels, with lung tissue having the highest GXM organ levels, localized primarily to alveolar macrophages. The results indicate that (i) intravenous administration to rats produced persistent serum GXM levels with a half-life similar to that found in mice and rabbits; (ii) endotracheal administration of GXM resulted in low serum levels; (iii) in the absence of specific antibody, GXM organ deposition occurs primarily in the spleen and is localized primarily to marginal zone macrophages; (iv) in the presence of specific immunoglobulin G1 antibody, GXM organ deposition occurs primarily in the liver and is localized primarily to Kupffer cells; and (vi) reticuloendothelial cells sequester GXM in the presence and absence of specific antibody.