The heterodimeric transferrin receptors of Trypanosoma brucei (Tf-Rs) are encoded by two genes termed ESAG7 and ESAG6. These genes belong to polycistronic transcription units contained in the multiple expression sites for the variant surface glycoprotein (VSG ESs), only one of which is active at a time. Each VSG ES carries a different copy of these genes, leading to alternative expression of Tf-Rs with quite distinct binding affinities for transferrins from various mammals. T. brucei clones exhibit marked growth differences depending on the species-specificity of the serum. Since transferrin is a vital growth factor for the parasite, we investigated whether it could be responsible for these observations. We analyzed the cases of Tf-Rs from two ESs preferentially selected for expression in man and mouse, respectively. We show that serum-dependent growth variations of trypanosomes expressing these receptors are independent of transferrin, and that both high- and low-affinity Tf-Rs allow efficient trypanosome growth in various sera, either in vivo or in vitro.