Trypanosoma brucei, the causative agent of African sleeping sickness, evades the immune response by expressing a coat of variant surface glycoprotein (VSG). VSG is expressed from a single telomeric expression site (ES), along with a number of expression site associated genes (ESAGs). Thus far, the function of most ESAGs is unknown. One ES contains the serum resistance associated gene (SRA), which confers resistance to trypanosome lytic factor in T. b. rhodesiense. Only three other ESAGs -5, 6 and 7 - are present in this ES. ESAGs 6 and 7 encode a heterodimeric transferrin receptor, but the function of ESAG5 has not been identified. We present here a bioinformatic analysis of ESAG5 and distinguish between T. brucei-specific ESAGs and Genes Related to ESAG5 (GRESAGs), which occur outside of ESs in chromosomal-internal contexts. Further, a genome-wide survey of these genes across kinetoplastids identifies a family of GRESAG5s in a number of species. Analysis of phylogenetic relationships indicates that this family may have evolved from a single ancestral copy. Predicted properties of (GR)ESAG5 proteins indicate a glycosylated protein containing either a signal peptide or transmembrane domain. Further analysis indicates a possible relationship to the lipid transfer/lipopolysaccharide-binding family which includes the bactericidal/permeability increasing (BPI) protein. Together, these results provide insights into the structure and evolution of an important extended gene family, and present a number of testable hypotheses which will aid in elucidating the function of ESAG5.