Abstract Siglecs (Sialic acid-binding Immunoglobulin-like Lectins) are vertebrate sialic acid (Sia) binding proteins mostly expressed in hematopoietic and immune cells. They are type-I proteins with an extracellular N-terminal Sia-binding Ig-like V-set domain, one or more C2-set Ig-like domains, a transmembrane domain and a C-terminal cytoplasmic tail. CD33-related Siglecs (CD33rSiglecs) are a genetically clustered subgroup. Prior comparative genomic analysis indicated accelerated evolution of CD33rSiglecs selectively occurring in the Sia-binding V-set domain, suggesting that this domain is under the greatest selection pressure. To gain further insight into this rapid evolution of CD33rSiglecs, we prepared recombinant form of the N-terminal domains of CD33rSiglecs from human, chimpanzee, and baboon, and compared their sialoglycan binding-specificities. Using ELISA on a panel of gangliosides or analysis on a sialoglycan microarray we show that binding patterns are widely divergent between the three species. Some show preference to Neu5Gc over Neu5Ac, especially in chimpanzees and baboons, indicating an evolutionary adjustment to the loss of Neu5Gc expression in humans. Expression patterns of CD33rSiglecs on circulating blood cells of humans and related great apes also show evidence for rapid evolution, and overall expression is greater in apes compared to human. The selection mechanisms driving this rapid evolution will be discussed.