There is a generic relationship between early changes in peripheral blood eosinophil counts (EOS)and the development of clinically significant rejection following solid organ transplantation. In a randomized, controlled trial of EOS monitoring in 80 heart transplant (HTx) recipients we have further shown that suppression of EOS can be used as a highly cost-effective guide to corticosteroid administration in the control of rejection within the first 6 post-operative weeks. We have now assessed the relative impact of immunosuppressive drugs, including the plasma prednisolone (PRL)concentration (HPLC assay), as well as plasma concentrations of two eosinophil chemotactic and activating peptides that act through the CC-chemokine receptor-3 (CCR3), eotaxin and RANTES (immunometric assay), on the diagnostic changes in EOS that precede treated HTx rejection (usually ISHLT Grade ≥ 3A). The first 46 consecutive HTx recipients recruited to our randomised trial, with a median follow-up of 90 days, were included in the study. Univariate regression analysis showed that cyclosporin dose, blood cyclosporin concentration, azathioprine dose and plasma RANTES concentration were not related to EOS. Factors related to changes in EOS included plasma PRL, endogenous cortisol and eotaxin concentrations. Multivariate linear regression analysis, accounting for within and between-patient correlations, revealed that the most important factors influencing EOS were PRL (-31% change in EOS per 50μg/L increase in PRL; 95% CI −21, -40%; P<0.001) and eotaxin (+22% change in EOS per 100μg/L increase in eotaxin; 95% CI +6, +41%; P=0.006) in a negative and positive manner, respectively. Changes in EOS that precede HTx rejection are controlled by a balance between eotaxin-induced mobilisation and corticosteroid-induced suppression. The use of new selective CCR3 antagonists may help to elucidate the pathophysiological significance of eosinophils in allograft rejection.