The genomic organization of a gene family for the invariant surface glycoprotein, ISG75 (invariant surface glycoprotein with a molecular mass of 75 kDa), from Trypanosoma brucei is described. In T. brucei strain 427 ISG75 genes are present in tandem arrays at two loci, A and B, containing 5 and 2 copies, respectively. At the S'-end of locus A, a single gene was identified that encodes a structural isoform of ISG75. This isoform contains a unique amino-terminal domain, whereas the rest of the protein is nearly identical to the polypeptides encoded by the other genes. This isoform is transcribed into a stable mRNA, but the expression of the derived polypeptide was below the detection limit. The ISG75 gene clusters are present on chromosomal bands 9' and 10, supporting the hypothesis of Gottesdiener et al. [25] that these bands contain allelic chromosomes. The total number of ISG75 genes is strain dependent, but at least one copy of the unique isoform is present in every variant tested.