Cryptococcus neoformans is surrounded by a capsular polysaccharide that inhibits phagocytosis of the yeast by macrophages. This capsular polysaccharide also confers several physicochemical properties to the cell surface, including a negative surface charge and a hydrophilic surface. The present study was designed to determine whether a hydrophobic surface was necessary or sufficient for phagocytosis of C. neoformans cells. The hydrophobic nature of the cell surface was measured by hydrophobic interaction chromatography on octyl-Sepharose. Liability to phagocytosis was determined by use of mouse peritoneal macrophages. The surface properties of C. neoformans cells were modified by (i) preincubation of cryptococcal cells with nonimmune serum or immune anticapsular serum, (ii) chemical modification of the carboxyl and O-acetyl groups in the capsular polysaccharide, and (iii) use of various serotypes of C. neoformans with different degrees of O-acetyl and xylosyl substitution. The results showed that it was possible to experimentally vary the surface hydrophobic-hydrophilic characteristics of the cell surface; however, the antiphagocytic character of the capsule remained unchanged. The results further suggest that a hydrophobic surface was neither necessary nor sufficient for phagocytosis of C. neoformans cells by macrophages.