The fate of microbial polysaccharides in host tissues is an important consideration because these compounds are often immune modulators. Splenic marginal zone macrophages that express the C-type lectin receptor SIGN-R1, take up neutral polysaccharides such as dextran and the capsular polysaccharide of Streptococcus pneumoniae. Given that the major component of Cryptococcus neoformans capsular polysaccharide, glucuronoxylomannan (GXM), localizes in the spleen when injected intravenously, we investigated whether GXM uptake was mediated by splenic macrophages expressing the SIGN-R1 receptor in mice. No significant differences in the amount and location of GXM deposition were detected in the spleens of mice treated with a SIGN-R1 blocking antibody when compared to controls. Similarly, a blocking antibody to Dectin-1, a co-receptor of -SIGN-R1, had no effects on GXM distribution within the spleen. Histological examination of spleens from mice and rats injected with FITC-Dextran and GXM revealed no significant co-localization, with Dextran and GXM being found in marginal and red pulp macrophages, respectively. Hence we conclude that GXM was not deposited in marginal zone macrophages. However, GXM deposition was found in the red pulp. These results indicate that there is a selective localization of these polysaccharides to different receptors such as SIGN-R1 for FITC dextran in marginal zone and a to-be-identified receptor selectively expressed by red pulp macrophages for GXM.